NO129093B - - Google Patents
Download PDFInfo
- Publication number
- NO129093B NO129093B NO02518/70A NO251870A NO129093B NO 129093 B NO129093 B NO 129093B NO 02518/70 A NO02518/70 A NO 02518/70A NO 251870 A NO251870 A NO 251870A NO 129093 B NO129093 B NO 129093B
- Authority
- NO
- Norway
- Prior art keywords
- groups
- stated
- triiodobenzoyl
- group
- acid
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 54
- 239000002872 contrast media Substances 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 125000001931 aliphatic group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 229960002442 glucosamine Drugs 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000003172 aldehyde group Chemical group 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 7
- 230000005484 gravity Effects 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- ZMZGFLUUZLELNE-UHFFFAOYSA-N 2,3,5-triiodobenzoic acid Chemical class OC(=O)C1=CC(I)=CC(I)=C1I ZMZGFLUUZLELNE-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 229960001413 acetanilide Drugs 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- 239000000243 solution Substances 0.000 description 41
- 239000002253 acid Substances 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- -1 alkali metal salts Chemical class 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 150000004820 halides Chemical class 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000003921 oil Substances 0.000 description 8
- 230000003204 osmotic effect Effects 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 231100000419 toxicity Toxicity 0.000 description 8
- 230000001988 toxicity Effects 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 230000002526 effect on cardiovascular system Effects 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000012800 visualization Methods 0.000 description 5
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 239000003957 anion exchange resin Substances 0.000 description 4
- 239000012736 aqueous medium Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000006192 iodination reaction Methods 0.000 description 4
- 150000008040 ionic compounds Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 230000002152 alkylating effect Effects 0.000 description 3
- 210000000748 cardiovascular system Anatomy 0.000 description 3
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 3
- 229920001429 chelating resin Polymers 0.000 description 3
- 150000004292 cyclic ethers Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 230000026045 iodination Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- CBOJBBMQJBVCMW-BTVCFUMJSA-N (2r,3r,4s,5r)-2-amino-3,4,5,6-tetrahydroxyhexanal;hydrochloride Chemical compound Cl.O=C[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO CBOJBBMQJBVCMW-BTVCFUMJSA-N 0.000 description 2
- SPYXCBRPFJVOTD-XKAARJIMSA-N 2,4,6-triiodo-n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]benzamide Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CN(C)C(=O)C1=C(I)C=C(I)C=C1I SPYXCBRPFJVOTD-XKAARJIMSA-N 0.000 description 2
- HRMQJJGGCUYILB-UHFFFAOYSA-N 2,4,6-triiodobenzoyl chloride Chemical compound ClC(=O)C1=C(I)C=C(I)C=C1I HRMQJJGGCUYILB-UHFFFAOYSA-N 0.000 description 2
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 2
- RSCMSACQRPYYRN-UHFFFAOYSA-N 3,5-diaminobenzamide Chemical compound NC(=O)C1=CC(N)=CC(N)=C1 RSCMSACQRPYYRN-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003729 cation exchange resin Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960001911 glucosamine hydrochloride Drugs 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 150000008146 mannosides Chemical class 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- VQSVOQJUFSROBP-LXGUWJNJSA-N (2r,3r,4r,5s)-6-(2-hydroxyethylamino)hexane-1,2,3,4,5-pentol Chemical compound OCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO VQSVOQJUFSROBP-LXGUWJNJSA-N 0.000 description 1
- XDIYNQZUNSSENW-RPQBYJBYSA-N (2s,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O XDIYNQZUNSSENW-RPQBYJBYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- CRVYPNHLIAWRNV-UHFFFAOYSA-N 2,4,6-triiodobenzoic acid Chemical compound OC(=O)C1=C(I)C=C(I)C=C1I CRVYPNHLIAWRNV-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- SEJCXXXEYJMYKT-NCCMUGIUSA-N 3,5-diamino-2,4,6-triiodo-n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]benzamide Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CN(C)C(=O)C1=C(I)C(N)=C(I)C(N)=C1I SEJCXXXEYJMYKT-NCCMUGIUSA-N 0.000 description 1
- UUKWKUSGGZNXGA-UHFFFAOYSA-N 3,5-dinitrobenzamide Chemical compound NC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 UUKWKUSGGZNXGA-UHFFFAOYSA-N 0.000 description 1
- NNOHXABAQAGKRZ-UHFFFAOYSA-N 3,5-dinitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC(C(Cl)=O)=CC([N+]([O-])=O)=C1 NNOHXABAQAGKRZ-UHFFFAOYSA-N 0.000 description 1
- GGOPTDHVLCAOSV-UHFFFAOYSA-N 3-(diacetylamino)-2,4,6-triiodobenzoic acid Chemical compound CC(=O)N(C(C)=O)C1=C(I)C=C(I)C(C(O)=O)=C1I GGOPTDHVLCAOSV-UHFFFAOYSA-N 0.000 description 1
- CPRGSOYWINBLDR-UHFFFAOYSA-N 3-amino-5-nitrobenzamide Chemical compound NC(=O)C1=CC(N)=CC([N+]([O-])=O)=C1 CPRGSOYWINBLDR-UHFFFAOYSA-N 0.000 description 1
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ZSBDPRIWBYHIAF-UHFFFAOYSA-N N-acetyl-acetamide Natural products CC(=O)NC(C)=O ZSBDPRIWBYHIAF-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- XWFMOWRKOWOJJN-UHFFFAOYSA-N [Na].ClICl Chemical compound [Na].ClICl XWFMOWRKOWOJJN-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229940023913 cation exchange resins Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000011208 chromatographic data Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000004990 dihydroxyalkyl group Chemical group 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000005188 flotation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002373 hemiacetals Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- RDFJFVXMRYVOAC-UHFFFAOYSA-N methiodal Chemical compound OS(=O)(=O)CI RDFJFVXMRYVOAC-UHFFFAOYSA-N 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000009608 myelography Methods 0.000 description 1
- ZEIPVGFKLCGLRR-UMSGYPCISA-N n-methyl-3,5-dinitro-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]benzamide Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CN(C)C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 ZEIPVGFKLCGLRR-UMSGYPCISA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 101150009274 nhr-1 gene Proteins 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000008278 pentosamines Chemical class 0.000 description 1
- 150000008379 phenol ethers Chemical class 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000003156 secondary amide group Chemical group 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000002330 subarachnoid space Anatomy 0.000 description 1
- 150000005846 sugar alcohols Chemical group 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical group OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003142 tertiary amide group Chemical group 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Trijodbenzoesyrederivater til bruk som Triiodobenzoic acid derivatives for use as
røntgenkontrastmidler og til bruk i oppløsninger med h^y egenvekt for anvendelse ved biologisk separering. X-ray contrast agents and for use in solutions with high specific gravity for use in biological separation.
Foreliggende oppfinnelse vedrører nye trijodbenzoesyrederivater til bruk som røntgenkontrastmidler og til bruk i oppløs-ninger med høy egenvekt for anvendelse ved biologisk separering. The present invention relates to new triiodobenzoic acid derivatives for use as X-ray contrast agents and for use in solutions with a high specific gravity for use in biological separation.
Ved røntgen synliggjørelse av relativt store områder i det menneskelige legeme, f.eks. det kardiovaskulære system, eller det rom som inneholder den cerebrospinale væske, må store mengder av røntgenkontrastmidler med høy konsentrasjon injiseres for å tilveiebringe en tilstrekkelig tetthet i det område som det dreier seg om. Følgelig er toksisiteten av kontrastmidlet ved høye konsentrasjoner av stor betydning. For synliggjøreIse i det kardiovaskulære system er et stort antall forbindelser blitt foreslått som kontrastmidler og selv om mange av disse er blitt anvendt med godt resultat så medfører dog deres toksisitet, skjønt den ofte er ganske liten, en del uønskede bieffekter. Ved synlig-gjørelse av det rom som inneholder den cerebrospinale væske er de høykonsentrerte forbindelser som anvendes ved kardiovaskulær synliggjørelse ofte altfor toksiske, hvilket skal forklares i det følgende. When X-rays make relatively large areas of the human body visible, e.g. the cardiovascular system, or the space containing the cerebrospinal fluid, large amounts of high-concentration X-ray contrast agents must be injected to provide sufficient density in the area concerned. Consequently, the toxicity of the contrast agent at high concentrations is of great importance. To make Ise visible in the cardiovascular system, a large number of compounds have been proposed as contrast agents, and although many of these have been used with good results, their toxicity, although it is often quite small, entails a number of unwanted side effects. When visualizing the space containing the cerebrospinal fluid, the highly concentrated compounds used for cardiovascular visualization are often far too toxic, which will be explained below.
Det ideelle kontrastmiddel for det subarachnoidale rom er ennu ikke blitt funnet. Gasser og oljer er blitt foreslått, men disse har mange ulemper. Det vann-oppløselige jodmetan-sulfonat er det prinsipielle vanlige kontrastmiddel for dette området, det har høy tetthet og absorberes ganske hurtig. Denne substans er imidlertid langt fra ideell, ved synliggjørelse av de forskjellige soner i det subarachoidale rom anvendes det vanligvis for radiculografi, men samtidig anvendelse av et anestetisk middel er nødvendig og det er for toksisk for cisternografi, ventrikkelgrafi og cervikal eller thorako myélografi. The ideal contrast agent for the subarachnoid space has not yet been found. Gases and oils have been proposed, but these have many disadvantages. The water-soluble iodomethane sulphonate is the principle common contrast agent for this area, it has a high density and is absorbed quite quickly. However, this substance is far from ideal, when highlighting the different zones in the subarachoid space it is usually used for radiculography, but the simultaneous use of an anesthetic agent is necessary and it is too toxic for cisternography, ventriculography and cervical or thoracomyelography.
Som antydet ovenfor velges de joderte forbindelser som vanligvis anvendes i det kardiovaskulære system vanligvis som følge av deres høye oppløselighet i vann, oppløselighet av størrelsesorden 100 g/100 ml er vanlig. For å oppnå vannoppløselig-het har man vanligvis valgt forbindelser som bærer en sur gruppe, f.eks. en karboksylsyregruppe eller en sulfonsyregruppe, da derés alkalimetallsalter og visse aminsalter ofte er overordentlig lett vannoppløselige og selv om flere av de kommersielt anvendte kontrastmidler av denne type oppviser en overordentlig lav toksisitetsgrad . intravenøst, så har deres anvendelse ved høye konsentrasjoner vist seg å føre til uønskede bieffekter når de utfelles i den cerebrospinale væske. Foruten de toksiske effekter som skyldes ionene er det blitt påvist at disse bieffekter delvis .skyldes osmotisk ubalanse som frembringes ved å injisere meget store konsentrasjoner av oppløst materiale i legemsvæskene. As indicated above, the iodinated compounds commonly used in the cardiovascular system are usually chosen because of their high solubility in water, solubilities of the order of 100 g/100 ml being common. In order to achieve water solubility, compounds which carry an acidic group have usually been chosen, e.g. a carboxylic acid group or a sulphonic acid group, as their alkali metal salts and certain amine salts are often extremely easily water-soluble and even though several of the commercially used contrast agents of this type exhibit an extremely low degree of toxicity. intravenously, their use at high concentrations has been shown to lead to undesirable side effects when they precipitate in the cerebrospinal fluid. In addition to the toxic effects caused by the ions, it has been demonstrated that these side effects are partly due to osmotic imbalance produced by injecting very large concentrations of dissolved material into the body fluids.
Det osmotiske trykk av en oppløsning av en kjemisk forbindelse er vanligvis tilnærmet direkte proporsjonal med summen av konsentrasjonene av de forskjellige molekylære eller ioniske stoffer som er tilstede. Et vann-oppløselig salt, f.eks. natrium-saltet av en jodert syre, vil normalt være nesten fullstendig ionisert og det osmotiske trykk vil være proporsjonalt med konsentrasjonen av både anionet og kationet. Den totale konsentrasjon av ioniske stoffer vil således være omtrentlig to ganger konsentrasjonen av saltet betraktet som en eneste ikke-ionisert substans. I motsetning hertil må man vente at det osmotiske trykk av en ikke-ionisert forbindelse, dvs. en forbindelse som er i alt vesentlig ikke-ionisert i vandig oppløsning er tilnærmet proporsjonalt ganske enkelt med molariteten av den tilstedeværende forbindelse, dvs. omtrent halvparten av verdien for en analog ioni- The osmotic pressure of a solution of a chemical compound is usually approximately directly proportional to the sum of the concentrations of the various molecular or ionic substances present. A water-soluble salt, e.g. the sodium salt of an iodinated acid will normally be almost completely ionized and the osmotic pressure will be proportional to the concentration of both the anion and the cation. The total concentration of ionic substances will thus be approximately twice the concentration of the salt considered as a single non-ionized substance. In contrast, one would expect that the osmotic pressure of a non-ionized compound, i.e. a compound that is substantially non-ionized in aqueous solution, is approximately proportional simply to the molarity of the compound present, i.e. approximately half the value for an analogous ioni-
sert forbindelse som oppviser to ioniserte deler. serted compound that exhibits two ionized moieties.
Våre undersøkelser av det osmotiske trykk har faktisk Our investigations of the osmotic pressure have actually
vist at den gruppe av ikke-ioniserte forbindelser i henhold til oppfinnelsen som er definert mer nøye i det følgende, oppviser verdier for det osmotiske trykk som er betydelig lavere enn de som man skulle vente på det ovennevnte grunnlag. shown that the group of non-ionized compounds according to the invention which is defined more carefully in the following, exhibits values for the osmotic pressure which are considerably lower than those which one would expect on the above-mentioned basis.
Vi har nå undersøkt et større antall av ikke-ioniserte joderte forbindelser og har kunnet fastslå at, i det spesielle følsomme område ved cerebrospinal synliggjørelse er toksisiteten av deres konsentrerte, vandige oppløsninger generelt meget bety- We have now examined a larger number of non-ionized iodinated compounds and have been able to determine that, in the particularly sensitive area of cerebrospinal visualization, the toxicity of their concentrated, aqueous solutions is generally very significant.
delig lavere enn toksisiteten for de beste ioniske forbindelser som er foreslått for bruk for et slikt formål og er generelt lavere enn toksisiteten for oppløsninger av de tilsvarende ion- substantially lower than the toxicity of the best ionic compounds proposed for use for such a purpose and is generally lower than the toxicity of solutions of the corresponding ionic compounds
iserte forbindelser»ized connections»
Mange av forbindelsene oppviser videre intravenøse toksisiteter som er utpreget lavere enn toksisiteten for de beste kommersielle vaskulære kontrastmidler, og er følgelig ytterligere verdifulle ved kardiovaskulær synliggjørelse. Many of the compounds further exhibit intravenous toxicities that are markedly lower than the toxicity of the best commercial vascular contrast agents, and are consequently of further value in cardiovascular imaging.
Våre undersøkelser har videre ført oss til den slutning Our investigations have further led us to that conclusion
at den joderte forbindelse bør være en alkanol som bærer i det minste en N-bundet sekundær eller tertiær amidgruppe. Dessuten skal molekylet oppvise i det minste to hydroksylgrupper. that the iodinated compound should be an alkanol bearing at least one N-linked secondary or tertiary amide group. In addition, the molecule must have at least two hydroxyl groups.
I henhold til foreliggende oppfinnelse tilveiebringes trijodbenzoesyrederivater til bruk som røntgenkontrastmidler og til bruk i oppløsninger med høy egenvekt for anvendelse ved biologisk separering, som har den generelle formel According to the present invention, triiodobenzoic acid derivatives for use as X-ray contrast agents and for use in high specific gravity solutions for use in biological separation are provided, which have the general formula
12 12
hvor R og R , som kan være de samme eller forskjellige, er hydrogenatomer eller alkylgrupper som eventuelt er substituert med hydroksy-, alifatisk acyioksy- og/eller aldehydgrupper, idet de ikke begge samtidig kan være hydrogen, og R<3> og R<4>, som kan være de samme eller forskjellige, er hydrogenatomer, acylaminogrupper av formelen NR 5 Ac hvor R <5>er et hydrogenatom eller en alkylgruppe som eventuelt er substituert med hydroksy-, alifatisk acyioksy- og/eller aldehydgrupper, eller en alifatisk acylgruppe og Ac er en alifatisk acylgruppe, acylaminometylgrupper av formelen where R and R , which can be the same or different, are hydrogen atoms or alkyl groups which are optionally substituted with hydroxy, aliphatic acyoxy and/or aldehyde groups, as they cannot both be hydrogen at the same time, and R<3> and R< 4>, which may be the same or different, are hydrogen atoms, acylamino groups of the formula NR 5 Ac where R <5> is a hydrogen atom or an alkyl group optionally substituted with hydroxy, aliphatic acyloxy and/or aldehyde groups, or an aliphatic acyl group and Ac is an aliphatic acyl group, acylaminomethyl groups of the formula
5 5 5 5
CH-NR Ac hvor R og Ac har den ovenfor anførte betydning, eller karbamoylgrupper av formelen CONR 6 R 7 hvor R <6> og R <7>er hydrogenatomer eller alkylgrupper som eventuelt er substituert med hydroksy-, alifatisk acyioksy- og/eller aldehydgrupper, og tilsvarende binukleære forbindelser inneholdende to ringstrukturer med formel i bundet sammen med en felles substituent, idet en hvilken som helst alkylgruppe, substituert alkylgruppe eller alifatisk acylgruppe som er tilstede, inneholder 1-6 karbonatomer, og det er tilstede i det minste én N-hydroksyalkylgruppe og i det minste to hydroksylgrupper i molekylet. CH-NR Ac where R and Ac have the meaning stated above, or carbamoyl groups of the formula CONR 6 R 7 where R <6> and R <7> are hydrogen atoms or alkyl groups which are optionally substituted with hydroxy-, aliphatic acyoxy- and/or aldehyde groups, and corresponding binuclear compounds containing two ring structures of formula i bonded together by a common substituent, wherein any alkyl group, substituted alkyl group or aliphatic acyl group present contains 1-6 carbon atoms, and at least one N is present -hydroxyalkyl group and at least two hydroxyl groups in the molecule.
Hydroksyalkylgruppene som er tilstede , kan bære en en-kel hydroksygruppe, som i /3-hydroksyetylgruppen, eller mere enn en hydroksygruppe, som i dihydroksypropyl eller tris-(hydroksy-metyl)-metylgruppen eller i polyhydroksyalkyldelen av heksoami-ner, pentosaminer, og aminosukkeralkoholer, som f.eks. glukosamin eller glukaminer, f.eks. N-metylglukamin, 1-glukamin eller 2-glukamin. Andre ikke-ioniske substituenter kan også være tilstede, f.eks. aldehydgruppen som er tilstede i glukosamin, eller en eller flere acyloksygrupper. The hydroxyalkyl groups that are present can carry a single hydroxy group, as in the /3-hydroxyethyl group, or more than one hydroxy group, as in the dihydroxypropyl or tris-(hydroxymethyl)methyl group or in the polyhydroxyalkyl portion of hexoamines, pentosamines, and amino sugar alcohols, such as glucosamine or glucamines, e.g. N-methylglucamine, 1-glucamine or 2-glucamine. Other non-ionic substituents may also be present, e.g. the aldehyde group present in glucosamine, or one or more acyloxy groups.
Alkyl-, hydroksyalkyl-og alifatiske acylgrupper som Alkyl, hydroxyalkyl and aliphatic acyl groups such as
er tilstede, inneholder 1-6 karbonatomer. Foretrukne alkylgrupper omfatter således metyl-, etyl-, propyl-, butyl- is present, contains 1-6 carbon atoms. Preferred alkyl groups thus include methyl, ethyl, propyl, butyl
og heksylgrupper, metylgruppen foretrekkes og en N-metyl-substituent øker ofte vannoppløseligheten„ and hexyl groups, the methyl group is preferred and an N-methyl substituent often increases water solubility„
Foretrukne acylgrupper som kan være O-bundet eller N-bundet, omfatter acetyl-, propionyl- og butyl-grupper, acetyl-gruppen er den som mest foretrekkes. Preferred acyl groups which may be O-linked or N-linked include acetyl, propionyl and butyl groups, the acetyl group being the most preferred.
Alkyl-, hydroksyalkyl- og acylgrupper som er tilstede, - kan dessuten bære en ytterligere ikke-ionisk jodert hydrokarbon-gruppe som kan bære ytterligere amidgrupper og således kan f.eks. en alkylen-, hydroksyalkylen- eller diacylgruppe som stammer fra en toverdig syre, være N-bundet ved hvilken som helst ende til identisk joderte hydrokarboner som bærer amidgrupper. Alkyl, hydroxyalkyl and acyl groups which are present - can also carry a further non-ionic iodinated hydrocarbon group which can carry further amide groups and thus can e.g. an alkylene, hydroxyalkylene or diacyl group derived from a divalent acid, be N-bonded at any end to identically iodinated hydrocarbons bearing amide groups.
Et antall av forbindelser i henhold til oppfinnelsen A number of compounds according to the invention
som er blitt fremstilt, er oppført i den nedenstående tabell I. that have been produced are listed in Table I below.
Som anført ovenfor har de nye ikke-ioniske forbindelser i henhold til oppfinnelsen vist utpreget lav toksisitet, særlig ved intracerebrale forsøk. Den nedenstående tabell 2 viser re-sultater oppnådd med et antall av forbindelser i henhold til oppfinnelsen sammenlignet med tidligere kjente røntgenkontrastmidler. Det vil sees at alle de nye forbindelser som er oppført er meget bedre enn de kjente forbindelser ved det intracerebrale forsøk. As stated above, the new non-ionic compounds according to the invention have shown distinctly low toxicity, particularly in intracerebral experiments. Table 2 below shows results obtained with a number of compounds according to the invention compared to previously known X-ray contrast agents. It will be seen that all the new compounds listed are much better than the known compounds in the intracerebral experiment.
De fleste av forbindelsene var så indifferente eller iner-te at det ikke var fysisk mulig å injisere en tilstrekkelig mengde substans for å drepe 50% av musene og i slike tilfelle kan bare en minimumsverdi anføres for LD50- Most of the compounds were so indifferent or inert that it was not physically possible to inject a sufficient amount of substance to kill 50% of the mice and in such cases only a minimum value can be stated for the LD50
En rekke av de nye forbindelser utmerker seg ved en meget høy vannoppløselighet. Vannoppløseligheten er vist i den nedenstående tabell 3. A number of the new compounds are distinguished by a very high water solubility. The water solubility is shown in table 3 below.
Det vil videre sees at de forbindelser som er vist i tabell 3 som oppviser 3 eller flere hydroksylgrupper, bortsett fra når det er tilstede et sekundært amid eller en estergruppe, er høy-vannoppløselige og disse foretrekkes generelt. It will further be seen that the compounds shown in Table 3 which exhibit 3 or more hydroxyl groups, except when a secondary amide or an ester group is present, are highly water soluble and these are generally preferred.
Det skal imidlertid bemerkes at selv om høy vannoppløse-lighet for mange formål er ønsket i et røntgenkontrastmiddel er ikke vannoppløseligheten av avgjørende betydning og forbindelser med en meget lav toksisitet kan være nyttige selv om de er vann-uoppløselige. However, it should be noted that although high water solubility is for many purposes desired in an X-ray contrast agent, water solubility is not of decisive importance and compounds with a very low toxicity may be useful even if they are water insoluble.
Som angitt ovenfor har forbindelsen i henhold til oppfinnelsen et lavt osmotisk trykk sammenlignet med de vanlig ioniske kontrastmidler og mange av forbindelsene oppviser endog en lavere osmotisk verdi enn man skulle vente. Den iakttatte osmose i hvert tilfelle skulle man vente ville være ca. 0,8 mol/ kg, men forbindelsene 3, 31, 33, 42 og 11 som er anført i tabell I har vist osmoseverdier av 0,47, 0,48, 0,61, 0,53 og 0,48 mol/kg ved 37°C (300 mg J/ml). De siste to forbindelser i tabell 2, som er ioniske forbindelser oppviser for sammenligningens skyld, osmoseverdier av ca. 1,6 mol/kg. As indicated above, the compound according to the invention has a low osmotic pressure compared to the usual ionic contrast agents and many of the compounds even show a lower osmotic value than one would expect. The observed osmosis in each case would be expected to be approx. 0.8 mol/kg, but the compounds 3, 31, 33, 42 and 11 listed in Table I have shown osmosis values of 0.47, 0.48, 0.61, 0.53 and 0.48 mol/kg at 37°C (300 mg J/ml). For the sake of comparison, the last two compounds in table 2, which are ionic compounds, show osmosis values of approx. 1.6 mol/kg.
Forbindelsene som er mest å foretrekke som kontrastmidler på det myelografiske område omfatter forbindelsene 6, 9, 10, 11, 12, 15 og 31 fra tabell I. The compounds most preferred as contrast agents in the myelographic area include compounds 6, 9, 10, 11, 12, 15 and 31 from Table I.
Disse forbindelser som er meget vann-oppløselige og er These compounds are highly water-soluble and are
i besittelse av aksepterbare viskositetsverdier er også nyttige som kardiovaskulæré kontrastmidler og forbindelsen 9 i tabell I ovenfor er særlig nyttig for dette formål da den oppviser en viskositet av 7,1 cp ved 20°C og en konsentrasjon av 300 mg j/ml. De foretrukne forbindelser som er anført ovenfor i forbindelse med det myelografiske område er imidlertid også meget nyttige for kardiovaskulær synligg jørelse som følge av deres overordentlig gode toleranse. possessing acceptable viscosity values are also useful as cardiovascular contrast agents and compound 9 in Table I above is particularly useful for this purpose as it exhibits a viscosity of 7.1 cp at 20°C and a concentration of 300 mg j/ml. However, the preferred compounds listed above in connection with the myelographic area are also very useful for cardiovascular imaging as a result of their exceedingly good tolerability.
Konsentrasjonen av røntgenkontrastmidlet i henhold til oppfinnelsen i vandig medium for administrering varierer med det spesielle anvendelsesformål. Generelt kreves lavere konsentrasjoner for ventrikkelgrafi enn for myelografi mens radi-crulgrafi krever enda lavere konsentrasjoner. Den foretrukne konsentrasjon og doseringsområder for forbindelsene for disse tre formål er som følger: The concentration of the X-ray contrast agent according to the invention in the aqueous medium for administration varies with the particular purpose of use. In general, lower concentrations are required for ventriculography than for myelography, while radiculography requires even lower concentrations. The preferred concentration and dosage ranges of the compounds for these three purposes are as follows:
Det foretrukne konsentrasjonsområde for kardiovaskulær synliggjørelse ar 150 - 450 mg J/ml. Mengden, av kontrastmidlet som skal administreres er fortrinnsvis slik at det vil The preferred concentration range for cardiovascular visualization is 150 - 450 mg J/ml. The amount of the contrast agent to be administered is preferably such that it will
forbli i systemet bare i ca. 2 til 3 timer, skjønt både kortere og lengere oppholdsperioder normalt er aksepterbare. Det aktive materiale må således for cerebrospinal synliggjørelse hensiktsmessig innføres i ampuller.som inneholder 5 - 15 ml av en vandig oppløsning av materialet, . men for vaskulær synliggjørelse, anvendes større mengder, f.eks. 10 til 500 ml. remain in the system only for approx. 2 to 3 hours, although both shorter and longer periods of stay are normally acceptable. For cerebrospinal visualization, the active material must therefore be suitably introduced into ampoules containing 5 - 15 ml of an aqueous solution of the material. but for vascular visualization, larger amounts are used, e.g. 10 to 500 ml.
De nye forbindelser i henhold til oppfinnelsen kan fremstilles på en hvilken som helst hensiktsmessig måte. The new compounds according to the invention can be prepared in any suitable way.
1) En særlig egnet fremgangsmåte omfatter reaksjon av en forbindelse av den generelle formel 1) A particularly suitable method comprises the reaction of a compound of the general formula
8 9 8 9
(hvor R og R som kan være dé samme eller forskjellige har (where R and R which can be the same or different have
3 4 — den betydning som ovenfor er gitt.for R og R , eller er kar-boksylgrupper) eller et amid-dannende derivat derav, med en for-12 12 3 4 — the meaning given above for R and R , or are carboxyl groups) or an amide-forming derivative thereof, with a pre-12 12
bindelse av formelen HNR R (hvor R og R har den ovenfor an- bond of the formula HNR R (where R and R have the above an-
førte betydning). Den foretrukne fremgangsmåte for utførelse av denne reaksjon er å kondensere et syrehalogenid, f.eks. bromidet, eller mere fordelaktig, kloridet, med forbindelsen av formelen NHR 1 R 2. brought meaning). The preferred method for carrying out this reaction is to condense an acid halide, e.g. the bromide, or more advantageously, the chloride, with the compound of the formula NHR 1 R 2 .
Reaksjonen utføres fortrinnsvis i et inert oppløsningsmiddel, som f.eks. en cyklisk eter, f.eks. dioksan eller tetrahydrofuran, The reaction is preferably carried out in an inert solvent, such as e.g. a cyclic ether, e.g. dioxane or tetrahydrofuran,
eller et amidoppløsningsmiddel, som dimetylformamid eller dimetylacetamid. Et lite overskudd av aminet anvendes fordelaktig og det kan være tilstede et syrebindende middel, f.eks. et alkalimetall-karbonat eller -bikarbonat: eller et tertiært amin, som trietanolamin. Et passende overskudd .av aminet kan imidlertid tjene'som syrebindende middel, eller når det er en væske, som. oppløsningsmiddel. or an amide solvent, such as dimethylformamide or dimethylacetamide. A small excess of the amine is advantageously used and an acid binding agent may be present, e.g. an alkali metal carbonate or bicarbonate: or a tertiary amine, such as triethanolamine. A suitable excess of the amine can, however, serve as an acid-binding agent, or when it is a liquid, which. solvent.
For isolering av karbamylforbindelsene,, kan residuet fra den inndampede reaksjonsblanding dispergeres i vann og syre av formel II regenerert ved hydrolyse av syrehalogenidet kan oppløses ved tilsetning av alkali. Når det er ønsket å: fjerne acylgruppene som anvendes for å beskytte hydroksylgrupper eller NH-grupper under dannelsen av syrehalogenidet, kan behandlingen med alkali utføres ved forhøyet temperatur, f.eks. 50-60°C. De mindre vann-oppløselige karbamylforbindelser kan fraskilles slike vandige oppløsninger. Når det dreier seg om mere vann-oppløselige karbamylforbindelser medfører imidlertid fraskillelsen fra anorganiske For isolation of the carbamyl compounds, the residue from the evaporated reaction mixture can be dispersed in water and acid of formula II regenerated by hydrolysis of the acid halide can be dissolved by addition of alkali. When it is desired to: remove the acyl groups used to protect hydroxyl groups or NH groups during the formation of the acid halide, the treatment with alkali can be carried out at an elevated temperature, e.g. 50-60°C. The less water-soluble carbamyl compounds can be separated from such aqueous solutions. When it comes to more water-soluble carbamyl compounds, however, the separation from inorganic compounds entails
salter, f.eks. slike som dannes mellom syrebindingsmidlet og det frigjorte hydrogenhalogenid, eller slike som dannes ved nøytrali-sering av syrehalogenidet, vanskeligheter. Under slike omstendig-heter kan den vannopplØselige karbamylforbindelse isoleres f.eks. ved fenolekstrahering. salts, e.g. such as are formed between the acid binding agent and the liberated hydrogen halide, or such as are formed by neutralization of the acid halide, difficulties. Under such circumstances, the water-soluble carbamyl compound can be isolated, e.g. by phenol extraction.
Residuet fra reaksjonsblandingen kan således oppløses i vann og om nødvendig behandles med alkali, slik som beskrevet ovenfor, hvoretter oppløsningen gjøres sur, f.eks. ved tilsetning av en mineralsyre, som saltsyre, f.eks. til en pH ca. 1 og ekstraheres med fenol. Fenolekstraksjonen utføres fortrinnsvis med en rekke særskilte ekstraksjoner, f.eks. 3 eller 4, og fenol-ekstraktene forenes. Hver fenolekstrakt er fordelaktig 1/10 til 1/5 av det vandige volum. Fenolen er fortrinnsvis 90% vandig fenol. De forenede fenolekstrakter vaskes derpå flere ganger, f.eks. 3-5 ganger, med vann for å ekstrahere gjenværende anorganiske salter, og det tilsettes ca. 2-3 vol-umdeler eter. Fenol/eter-oppløsningen ekstraheres derpå med vann, fortrinnsvis flere ganger, f.eks. 3-5 ganger, under anvendelse av 1/10 volumdel vann for hver ekstraksjon. Den vandige oppløsning vaskes derpå med eter for å fjerne gjenværende fenol og inndampes til tørrhet for å gi det ønskede kontrastmiddel. Det er også mulig å rense vannopplØselige kontrastmidler ved å bringe reaksjonsoppløsningen i kontakt med ioneutvekslingsharpikser, f. eks. kation-utvekslingsharpiksér foir å fjerne kationer fra syrebindingsmidlet og/eller anionutvekslings-harpikser for å fjerne syren frå det hydrolyserte syréhalogénid. The residue from the reaction mixture can thus be dissolved in water and, if necessary, treated with alkali, as described above, after which the solution is made acidic, e.g. by adding a mineral acid, such as hydrochloric acid, e.g. to a pH of approx. 1 and extracted with phenol. The phenol extraction is preferably carried out with a number of separate extractions, e.g. 3 or 4, and the phenol extracts are combined. Each phenolic extract is advantageously 1/10 to 1/5 of the aqueous volume. The phenol is preferably 90% aqueous phenol. The combined phenolic extracts are then washed several times, e.g. 3-5 times, with water to extract remaining inorganic salts, and approx. 2-3 parts by volume of ether. The phenol/ether solution is then extracted with water, preferably several times, e.g. 3-5 times, using 1/10 volume of water for each extraction. The aqueous solution is then washed with ether to remove residual phenol and evaporated to dryness to give the desired contrast agent. It is also possible to purify water-soluble contrast agents by bringing the reaction solution into contact with ion exchange resins, e.g. cation exchange resins to remove cations from the acid binder and/or anion exchange resins to remove the acid from the hydrolyzed acid halide.
Produktene kan også isoleres ved" ekstraksjon av reaksjonsblandingen, f.eks. med cykliske etere, som tetrahydrofuran eller dioksan. The products can also be isolated by extraction of the reaction mixture, for example with cyclic ethers, such as tetrahydrofuran or dioxane.
Syrehalogenidene av syrene av formel II, som selv er nye forbindelser, kan fremstilles ved reaksjon av syren med et halogeneringsmiddel, som tionylklorid eller -bromid, fosforpenta-klorid eller -bromid eller fosforoksyklorid eller -oksybromid. Et inert oppløsningsmiddel, f.eks. en cyklisk eter, som dioksan eller tetrahydrofuran eller et hydrokarbonoppløsningsmiddel, som f.eks. benzen eller toluen kan anvendes eller et overskudd av reagenset kan tjene som reaksjonsmedium. Når det er fri NH og/eller OH tilstede i utgangssyren kan disse imidlertid reagere med halogenerings-midlet og i slike tilfeller beskyttes de fortrinnsvis. Acylering er den mest hensiktsmessige form for beskyttelse, da både N-acyl og O-acyl-grupper kan tilsettes samtidig ved reaksjonen med et acyleringsmiddel, som f.eks. et acylhalogenid eller et anhydrid. Acylgruppene er fortrinnsvis alifatiske acylgrupper, som propionyl, eller mér fordelaktig, acetylgrupper. Hydroksylgruppené på sukker eller sukkeralkoholresiduer kan også beskyttes, f.eks. ved ketal dannelse. The acid halides of the acids of formula II, which are themselves new compounds, can be prepared by reacting the acid with a halogenating agent, such as thionyl chloride or bromide, phosphorus pentachloride or bromide or phosphorus oxychloride or oxybromide. An inert solvent, e.g. a cyclic ether, such as dioxane or tetrahydrofuran, or a hydrocarbon solvent, such as e.g. benzene or toluene can be used or an excess of the reagent can serve as the reaction medium. When free NH and/or OH are present in the starting acid, however, these can react with the halogenating agent and in such cases they are preferably protected. Acylation is the most appropriate form of protection, as both N-acyl and O-acyl groups can be added simultaneously during the reaction with an acylating agent, such as e.g. an acyl halide or an anhydride. The acyl groups are preferably aliphatic acyl groups, such as propionyl, or more advantageously, acetyl groups. Hydroxyl groups on sugar or sugar alcohol residues can also be protected, e.g. by ketal formation.
En særlig egnet klasse av beskyttende grupper er trialkyl-silylgrupper, f.eks. trimetylsilylgruppen. Alle de fri hydroksylgrupper i hydroksy-amin-reagenset kan hensiktsmessig beskyttes samtidig på denne måte, f.eks. ved reaksjon med trialkylsilyl-halogenid, f.eks. kloridet, fortrinnsvis véd lave temperaturer, f.eks. 0-20°C, for å unngå dannelse av N-derivater. Tertiære aminer som pyridin er særlig egnede oppløshingsmidler og tjener også som syrébindihgsmidler. Et inert oppløsningsmiddel som f.eks. en eter kan dessuten være tilstede. A particularly suitable class of protecting groups are trialkylsilyl groups, e.g. the trimethylsilyl group. All the free hydroxyl groups in the hydroxyamine reagent can be suitably protected simultaneously in this way, e.g. by reaction with trialkylsilyl halide, e.g. the chloride, preferably at low temperatures, e.g. 0-20°C, to avoid formation of N-derivatives. Tertiary amines such as pyridine are particularly suitable solvents and also serve as acid binders. An inert solvent such as an ether may also be present.
Som angitt tidligere kan disse beskyttende grupper få forbli under amid-dannelsen, mén kan fjernes deretter ved hydrolyse. As indicated earlier, these protective groups may remain during the amide formation, but can then be removed by hydrolysis.
Dé trialkylsilylbeskyttende grupper kan fjernes deretter ved hydrolyse med fortynnet syre, f.eks. en vandig alkoholisk opp-løsning av saltsyre ved en pH 2-3. Det er også mulig å danne syrehalbgénider ved halogenering av syrer av formel II som ikke har noen hydroksyalkylgrupper, og å innføre disse grupper deretter f.eks. i de nedenfor beskrevne fremgangsmåter. The trialkylsilyl protecting groups can then be removed by hydrolysis with dilute acid, e.g. an aqueous alcoholic solution of hydrochloric acid at a pH of 2-3. It is also possible to form acid half-genides by halogenation of acids of formula II which have no hydroxyalkyl groups, and to introduce these groups then e.g. in the methods described below.
2) En annen fremgangsmåte omfatter reaksjon av en forbindelse med den generelle formel III 2) Another method involves the reaction of a compound with the general formula III
12 4 12 4
(hvor R , R , R og. Ac har de ovenfor angitte betydninger) (where R , R , R and. Ac have the meanings given above)
med et alkylerende, acyloksyalkylerende eller hydroksylakyl-erende middel. "Alkylerings"-midlet kan f.eks. være et reaktivt -mono-ester-deriyat av en alkohol eller polyol, f.eks. et halogenid, f.eks. et klorid eller bromid, eller et sulfat eller et hydrokarbonsulfonat. For innføring av en hydroksyetylgruppe er 2-kloretanol et egnet middel. For.innføring av en metyl-gruppe, er dimetylsulfat et egnet middel. Det reaktive derivat bringes fortrinnsvis til å reagere med acylamidutgangsmaterialet under basiske betingelser, f.eks. i et vandig alkalisk medium, som f.eks. inneholder et alkalimetallhydroksyd, som natrium-eller kaliumhydroksyd, eller i et ikke-vandig medium, f.eks. i en aLkanol, som metanol eller etanol, basen er hensiktsmessig et alkalimetallalkoksyd, som natriummetoksyd. Det er også mulig å bringe acylamidforbindelsen til å reagere med et epoksyd, f.eks. etylenoksyd, propylenoksyd, glycid osv.,, fordelaktig i nøytral alkoholisk oppløsning. with an alkylating, acyloxyalkylating or hydroxyalkylating agent. The "alkylating" agent can e.g. be a reactive -mono-ester derivative of an alcohol or polyol, e.g. a halide, e.g. a chloride or bromide, or a sulfate or a hydrocarbon sulfonate. For introducing a hydroxyethyl group, 2-chloroethanol is a suitable agent. For the introduction of a methyl group, dimethyl sulfate is a suitable agent. The reactive derivative is preferably reacted with the acylamide starting material under basic conditions, e.g. in an aqueous alkaline medium, such as e.g. contains an alkali metal hydroxide, such as sodium or potassium hydroxide, or in a non-aqueous medium, e.g. in an alkanol, such as methanol or ethanol, the base is conveniently an alkali metal alkoxide, such as sodium methoxide. It is also possible to react the acylamide compound with an epoxide, e.g. ethylene oxide, propylene oxide, glycide, etc., advantageously in neutral alcoholic solution.
3) Reaksjon av .et jodert amid som angitt i 2) ovenfor og 3) Reaction of .an iodinated amide as indicated in 2) above and
som oppviser en NH-gruppe, f.eks. en karbamylforbindelse av formel III, medet allylerende middel, f.eks. et reaktivt derivat av. en allylalkphol, f.eks. allylklorid eller -bromid, for å innføre en Nrallylgruppe som derpå utsettes for oksydasjon av dens dobbeltbinding, f.eks..under anvendelse av et perman-ganat oksyderingsmiddel, for å danne en glykolgruppe, hvorved det dannes et ikke-ionisk amid med en. N-dihy.droksyaikylgruppe, f.eks. en,forbindelse av formel.I.i hvilken.er en dihydroksy-alkylgruppe, som en dihydroksypropylgruppe. which exhibits an NH group, e.g. a carbamyl compound of formula III, with an allylating agent, e.g. a reactive derivative of. an allyl alkphol, e.g. allyl chloride or bromide, to introduce an N-allyl group which is then subjected to oxidation of its double bond, e.g. using a permanganate oxidizing agent, to form a glycol group, thereby forming a non-ionic amide with a. N-dihydroxyalkyl group, e.g. a compound of formula I in which is a dihydroxyalkyl group, such as a dihydroxypropyl group.
4) En annen fremgangsmåte omfatter reaksjon av en forbindelse av formelen 4) Another method involves the reaction of a compound of the formula
med et acylerende middel etterfulgt av hydrolyse av eventuelt uønskede acyloksygrupper som dannes under reaksjonen. with an acylating agent followed by hydrolysis of any unwanted acyloxy groups that are formed during the reaction.
Acyleringsmidlet kan f.eks være et syreanhydrid (som The acylating agent can, for example, be an acid anhydride (such as
også kan tjene som oppløsningsmiddel) sammen med katalytiske mengder av en mineralsyre, f.eks. svovelsyre eller perklorsyre, eller et syrehalogenid fortrinnsvis i et polart oppløsningsmiddel, som dimetylformamid eller dimetylacetamid, syrehalogenider foretrekkes som følge av at det dannes mindre mengder av bi-produkter. Den basiske hydrolyse av O-acylgruppen kan f.eks. utføres ved anvendelse av et vandig alka,limetall-hydroksyd, f.eks. natriumhydroksyd og reaksjonen utføres fortrinnsvis ved romtemperatur. Alt etter det acyleringsmiddel som anvendes kan det dessuten dannes andre produkter som krever fraskillelse. Når et acylanhydrid, som eddiksyreanhydrid anvendes med konsentrert svovelsyre som katalysator, vil en primær amino- can also serve as a solvent) together with catalytic amounts of a mineral acid, e.g. sulfuric acid or perchloric acid, or an acid halide preferably in a polar solvent, such as dimethylformamide or dimethylacetamide, acid halides are preferred due to the fact that smaller amounts of by-products are formed. The basic hydrolysis of the O-acyl group can e.g. is carried out using an aqueous alkali metal hydroxide, e.g. sodium hydroxide and the reaction is preferably carried out at room temperature. Depending on the acylating agent used, other products may also be formed that require separation. When an acyl anhydride, such as acetic anhydride, is used with concentrated sulfuric acid as a catalyst, a primary amino-
gruppe ofte, delvis bli bis-acylert, skjønt bis-acylamino-gruppen meget lett hydrolyseres til acylamid under milde basiske betingelser. 5) Jodering av et benzoesyreamid som bærer i det minste en N-hydroksylalkylgruppe og som har i det minste to hydroksylgrupper i molekylet. Joderingen kan hensiktsmessig utføres under anvendelse av jod-monoklorid eller en kompleks forbindelse herav, som natriumjoddiklorid. Reaksjonen utføres fortrinnsvis i et vandig medium, fordelaktig ved sur pH. group often, partially become bis-acylated, although the bis-acylamino group is very easily hydrolyzed to acylamide under mild basic conditions. 5) Iodination of a benzoic acid amide which carries at least one N-hydroxylalkyl group and which has at least two hydroxyl groups in the molecule. The iodination can conveniently be carried out using iodine monochloride or a complex compound thereof, such as sodium iodine dichloride. The reaction is preferably carried out in an aqueous medium, advantageously at an acidic pH.
Benzoesyreamidet som anvendes som utgangsmateriale kan bære andre grupper i molekylet, men må ha alle tre 2-, 4- og 6-stillingene usubstituerte. 3- og/eller 5-stillingene kan The benzoic acid amide used as starting material can carry other groups in the molecule, but must have all three 2-, 4- and 6-positions unsubstituted. The 3 and/or 5 positions can
3 4 3 4
f.eks. bære gruppene R og R som angitt ovenfor i forbindelse med formel I, men i det minste en f iri NI^ -gruppe bør fortrinnsvis være tilstede. e.g. bear the groups R and R as indicated above in connection with formula I, but at least one 4 iri NI^ group should preferably be present.
Et 3,5-diamino-benzoesyreamid som bærer en N-hydroksyalkylgruppe og som har i det minste to hydroksylgrupper kan således f.eks. bringes til å reagere med et joderingsreagens hvorved det kan innføres jodatomer i 2-, 4- og 6-stillingene, de frie -grupper overføres deretter til avylaminogrupper med acylering, f.eks. under anvendelse av acyleringsmidler som syreanhydrider eller halogenider. A 3,5-diamino-benzoic acid amide which carries an N-hydroxyalkyl group and which has at least two hydroxyl groups can thus e.g. is made to react with an iodination reagent whereby iodine atoms can be introduced in the 2-, 4- and 6-positions, the free -groups are then transferred to avylamino groups with acylation, e.g. using acylating agents such as acid anhydrides or halides.
3,5-diamino-benzoesyreamidet kan fremstilles ved red-uksjon av det tilsvarende 3,5-dinitro-benzoesyreamid eller 3-amino-5-nitro-benzoesyreamidet, under anvendelse av reagenser som tjener til å redusere en nitrogruppe til en aminogruppe, f.eks. katalytisk hydrogenering, f.eks. under anvendelse av en palladiumkatalysator, hydrazin og Raneynikkel, eller reaksjon med en kilde for sulfit-, bisulfit- eller ditionitioner, f.eks. svoveldioksyd eller et alkalimetallsulfit, bisulfit eller ditionit i vandig medium, for å gi en sulfaminogruppe, NHS03H etterfult av hydrolyse for å gi en NI^ -gruppe (Piria reaksjon) f.eks.- under anvendelse av en mineralsyre som saltsyre. Sulfaminoforbindelsen kan imidlertid om ønskes bringes til å reagere med et alkylerénde, hydroksyalkylerende eller acyloksyalkylerende middel før hydrolysen, hvorved det dannes en alkylamino-, hydroksyalkylamino- eller acyioksy- The 3,5-diamino-benzoic acid amide can be prepared by reduction of the corresponding 3,5-dinitro-benzoic acid amide or the 3-amino-5-nitro-benzoic acid amide, using reagents which serve to reduce a nitro group to an amino group, f .ex. catalytic hydrogenation, e.g. using a palladium catalyst, hydrazine and Raney nickel, or reaction with a source of sulfite, bisulfite or dithionite ions, e.g. sulfur dioxide or an alkali metal sulphite, bisulphite or dithionite in an aqueous medium, to give a sulphamino group, NHS0 3 H followed by hydrolysis to give an NI^ group (Piria reaction) e.g.- using a mineral acid such as hydrochloric acid. However, the sulfamino compound can, if desired, be reacted with an alkylating, hydroxyalkylating or acyloxyalkylating agent before the hydrolysis, whereby an alkylamino-, hydroxyalkylamino- or acyloxy-
alkylaminogruppe. alkylamino group.
Amidutgangsforbindelsen kan fremstilles ved en fremgangsmåte analog med den ovenfor angitte under (1). The starting amide compound can be prepared by a method analogous to that stated above under (1).
Den foran nevnte joderingsreaksjon kan naturligvis utføres på frie benzoesyrer eller reaktive derivater herav, som halogenider eller estere, for å gi utgangsmaterialer for reaksjonen (1). The aforementioned iodination reaction can of course be carried out on free benzoic acids or reactive derivatives thereof, such as halides or esters, to provide starting materials for reaction (1).
Forbindelsene av formel I, og særlig slike hvor R<3> betyr gruppen NR 5AC er utsatt for en rekke av forskjellige typer av isomeri slik som forklart nedenfor. Oppfinnelsen omfatter alle slike isomere former. Idet det henvises til følgende formel The compounds of formula I, and especially those where R<3> means the group NR 5AC are subject to a number of different types of isomerism as explained below. The invention encompasses all such isomeric forms. Referring to the following formula
og bindingene som i denne er gitt nummerne 1-4, kan man skjelne mellom følgende formler for isomeri: and the bonds which in this are given the numbers 1-4, one can distinguish between the following formulas for isomerism:
(a) Ekso-endo isomeri som skyldes en begrenset rotering (a) Exo-endo isomerism due to a restricted rotation
av N-CO bindingen (3) forårsaket av sterisk hindring fra de tilgrensende store jodatomer. Disse isomerer har en tendens til å være i likevekt i oppløsning, men er tilstrekkelig stabile til å kunne adskilles ved tynnsjiktkromatografi, glukoamidet av N-metyl-3,5-bis-acetamid-2,4,6-trijodbenzoesyre består f.eks. av ca. 20% of the N-CO bond (3) caused by steric hindrance from the neighboring large iodine atoms. These isomers tend to be in equilibrium in solution, but are sufficiently stable to be separated by thin layer chromatography, the glucoamide of N-methyl-3,5-bis-acetamide-2,4,6-triiodobenzoic acid consists e.g. of approx. 20%
av endoformen og 80% av eksoformen. For at en slik isomeri skal foreligge må R 5 ikke være hydrogen. of the endoform and 80% of the exoform. For such an isomerism to exist, R 5 must not be hydrogen.
(b) Cis-trans isomeri som skyldes en begrenset rotering (b) Cis-trans isomerism due to a restricted rotation
av bindingene (1) og (2), forårsakes igjen av sterisk hindring fra det tilgrensende jodatomet. For at denne type av isomeri skal of bonds (1) and (2), is again caused by steric hindrance from the neighboring iodine atom. For this type of isomerism to
12 5 12 5
kunne foreligge er det nødvendig at ingen av> R , R og R er hydrogen. Mens bindingen 2 ikke synes å tillate noen rotasjon, synes likevekten av binding 1 å være mere lett tilgjengelig og hittil har man ikke kunnet adskille cis-trans isomerer. could be present, it is necessary that none of > R , R and R is hydrogen. While bond 2 does not seem to allow any rotation, the equilibrium of bond 1 seems to be more easily accessible and so far it has not been possible to separate cis-trans isomers.
(c) Syn-anti isomeri som skyldes begrenset rotering av C-N-bindingen (4). Naturligvis må R 1 og R 2 være forskjellige og ikke hydrogen. Motstandsevnen like overfor rotering av bindingen (4) (c) Syn-anti isomerism due to restricted rotation of the C-N bond (4). Naturally, R 1 and R 2 must be different and not hydrogen. The resistance to rotation of the bond (4)
er lignende den som for binding (3), men hittil har man ikke kunnet utføre noen kromatografisk adskillelse. is similar to that of bond (3), but so far no chromatographic separation has been possible.
o 12 o 12
Når gruppen -NR R er resten av et sukkeramin, så foreligger det to ytterligere typer av isomeri, nemlig: (d) Geometrisk isomeri av hemi-acetalbindingen i den cykliske sukkerform. Mutarotasjon er mulig slik at skjønt en form kan være i overskudd når amidet krystalliseres under nøytrale eller basiske betingelser, fører syrer til en proton-katalysert likevekt. Når optisk rotering bestemmes for å karakterisere et sukkeramid, skal produktet følgelig fortrinnsvis først bringes til likevekt i syre for å få en karakteristisk verdi som ikke er avhengig av til-stedeværelsen av et overskudd av en hemi-acetal isomer. (e) Optisk isomeri som følge av de optiske egenskaper av sukkeraminet. D-formene for sukkeraminet er blitt anvendt ved utførelsen av det foreliggende arbeide, men L-former kan på lignende måte anvendes. Denne type av isomeri foreligger naturligvis alltid når det er tilstede et asymmetrisk karbonatom og sukker-alkoholamidene eksisterer altså i D- eller L-formen. D-formene er også i dette tilfelle særlig blitt anvendt. When the group -NR R is the residue of a sugar amine, two further types of isomerism exist, namely: (d) Geometric isomerism of the hemiacetal bond in the cyclic sugar form. Mutarotation is possible so that although one form may be in excess when the amide is crystallized under neutral or basic conditions, acids lead to a proton-catalyzed equilibrium. Accordingly, when optical rotation is determined to characterize a sugar amide, the product should preferably first be equilibrated in acid to obtain a characteristic value which is not dependent on the presence of an excess of a hemiacetal isomer. (e) Optical isomerism due to the optical properties of the sugar amine. The D forms of the sugar amine have been used in the execution of the present work, but L forms can be used in a similar way. This type of isomerism naturally always exists when an asymmetric carbon atom is present and the sugar-alcohol amides therefore exist in the D or L form. The D-forms have also been particularly used in this case.
Når gruppen NR 1 R 2 stammer fra glukosamin, enda en type av isomeri er mulig, nemlig: (f) Glukose-mannose epimeri. Glukosamider kan bli utsatt for epimeri ved karbonatomet grensende til aldehydgruppen som er tilstede i den åpne kjedeform, som alltid sameksisterer i likevekt med den cykliske form. Denne epimerisering katalyseres av hydroksylioner og danner det tilsvarende mannosid. Ved syntese av glukosamider under alkaliske betingelser vil derfor vanligvis When the group NR 1 R 2 originates from glucosamine, yet another type of isomerism is possible, namely: (f) Glucose-mannose epimery. Glucosamides can undergo epimerism at the carbon atom adjacent to the aldehyde group present in the open chain form, which always coexists in equilibrium with the cyclic form. This epimerization is catalyzed by hydroxyl ions and forms the corresponding mannoside. In the synthesis of glucosamides under alkaline conditions will therefore usually
en mengde mannosid være tilstede i utgangsreaksjonsblandingen og kan fraskilles ved tynnsjiktkromatografi. For den praktiske anvendelse av røntgenkontrastforbindelsen er imidlertid en slik fraskillelse ikke nødvendig. a quantity of mannoside be present in the starting reaction mixture and can be separated by thin-layer chromatography. However, for the practical application of the X-ray contrast compound, such separation is not necessary.
Syrene av formel II er, i mange tilfeller, kjente forbindelser. Andre er beskrevet i det belgiske patent nr. 734257. Karbamylforbindelsen av formel III kan faktisk fåes for de tilsvarende syrer ved den ovenfor angitte fremgangsmåte (1). The acids of formula II are, in many cases, known compounds. Others are described in Belgian patent no. 734257. The carbamyl compound of formula III can actually be obtained for the corresponding acids by the above-mentioned method (1).
De sterkt vann-oppløselige forbindelser i henhold til oppfinnelsen kan som følge av deres store molekylvekt oppløses for å gi oppløsninger med en meget høy egenvekt. Slike opp-løsninger er særlig nyttige ved biologisk arbeidsteknikk hvorunder celler håndteres i oppløsninger av høy egenvekt, f.eks. ved sentrifugering eller differensial-fIotasjon fordi deres lave osmose reduserer osmolysen av cellene som finnes når konsentrerte oppløsninger av salter anvendes for dette formål. The highly water-soluble compounds according to the invention can, as a result of their large molecular weight, be dissolved to give solutions with a very high specific gravity. Such solutions are particularly useful in biological work techniques during which cells are handled in solutions of high specific gravity, e.g. by centrifugation or differential flotation because their low osmosis reduces the osmolysis of the cells that occurs when concentrated solutions of salts are used for this purpose.
Fremstilling av Manufacture of
( a) Utgangsmaterialer (a) Starting materials
(1) 3- amino- 5- N- metylacetamid- 2, 4, 6- trijodbenzoylklorid (1) 3- amino- 5- N- methylacetamide- 2, 4, 6- triiodobenzoyl chloride
3-amino-5-N-metylacetamid-2,4,6-trijodbenzoesyre (586 g, 3-amino-5-N-methylacetamide-2,4,6-triiodobenzoic acid (586 g,
1,0 mol) ble suspendert i tionylklorid (5 96 ml) og bragt til reaksjon ved omrøring ved 70°C i 16 timer. Overskudd av tionyl- 1.0 mol) was suspended in thionyl chloride (596 ml) and reacted with stirring at 70°C for 16 hours. Excess thionyl-
klorid ble destillert av i vakuum, residuet oppløst i kloroform (2500 ml) avkjølt i isbad, vasket med isvann (3 x 100 ml), mettet NaHC03 oppløsning (3 x 100 ml), 2n Na2C03 oppløsning (2 x 100 ml) chloride was distilled off in vacuo, the residue dissolved in chloroform (2500 mL) cooled in an ice bath, washed with ice water (3 x 100 mL), saturated NaHCO 3 solution (3 x 100 mL), 2n Na 2 CO 3 solution (2 x 100 mL)
og sluttlig med vann (3 x 100 ml) . Etter tørking med CaCl2 ble kloroformen destillert av og residuet tørket i vakuum. and finally with water (3 x 100 ml). After drying with CaCl2, the chloroform was distilled off and the residue dried in vacuo.
Utbytte: 522 g (91%), sm.p. 145-160°C. En prøve ble omkrystallisert fra etylacetat. Sm.p. 181-205°C. Funnet: Cl 5,37, beregnet for C10H8C1J3N20: Cl 5,88. (2) 3- amino- 5- N- metylacetamid- 2, 4, 6- trijodbenzoylklorid fremstilt ved anvendelse av PCI,.. Yield: 522 g (91%), m.p. 145-160°C. A sample was recrystallized from ethyl acetate. Sm.p. 181-205°C. Found: Cl 5.37, calculated for C10H8C1J3N20: Cl 5.88. (2) 3-amino-5-N-methylacetamide-2,4,6-triiodobenzoyl chloride prepared using PCI,..
3-amino-5-N-metylacetamid-2,4,6-trijodbenzoesyre (58,6 g, 3-amino-5-N-methylacetamide-2,4,6-triiodobenzoic acid (58.6 g,
0,1 mol) ble suspendert i toluen (50 ml) og benzen (25 ml). 0.1 mol) was suspended in toluene (50 mL) and benzene (25 mL).
Benzenet ble destillert av for å fjerne spor av vann. Fosforpenta-klorid (20,8 g, 0,1 mol) ble tilsatt under omrøring ved 40° og derpå opphetet til 70° og omrørt i 16 timer. Den nye krystallinske forbindelse falt ut før alt utgangsmateriale var oppløst. Reaksjonsblandingen ble lagret ved -20° før filtrering. The benzene was distilled off to remove traces of water. Phosphorus pentachloride (20.8 g, 0.1 mol) was added with stirring at 40° and then heated to 70° and stirred for 16 hours. The new crystalline compound precipitated before all the starting material had dissolved. The reaction mixture was stored at -20° before filtration.
Utbytte: 52,9 g (87%). Funnet: Cl 5,78, beregnet for C12H10<C>1J3N2°3: Cl 5,88. Yield: 52.9 g (87%). Found: Cl 5.78, calculated for C12H10<C>1J3N2°3: Cl 5.88.
(3) (a) 3- diacetylamino- 5- N- metylacetamid- 2, 4, 6- trijodbenzoylklorid (3) (a) 3- diacetylamino- 5- N- methylacetamide- 2, 4, 6- triiodobenzoyl chloride
Syrekloridet fra fremstilling 2 (80 g) ble suspendert i eddiksyreanhydrid (400 ml) og opphetet til 60°C. Konsentrert H2S04 (0,16 ml) ble tilsatt under omrøring og reaksjonsblandingen ble The acid chloride from Preparation 2 (80 g) was suspended in acetic anhydride (400 ml) and heated to 60°C. Concentrated H 2 SO 4 (0.16 mL) was added with stirring and the reaction mixture was
omrørt ved 100°C i 2 timer og ved romtemperatur over natten. Det filtrerte produkt ble suspendert i iseddiksyre, filtrert påny og tørket. Utbytte: 77 g (85%), sm.p. 255-260°C. Omkrystallisert fra dioksan smeltet forbindelsen ved 261-265°C. Funnet: C 24,84, H'2,12, N 4,10, Cl 5,2. Beregnet for C^H^CIJ^O^ C 24,43, stirred at 100°C for 2 hours and at room temperature overnight. The filtered product was suspended in glacial acetic acid, filtered again and dried. Yield: 77 g (85%), m.p. 255-260°C. Recrystallized from dioxane, the compound melted at 261-265°C. Found: C 24.84, H'2.12, N 4.10, Cl 5.2. Calculated for C^H^CIJ^O^ C 24.43,
H 1,76, N 4,07, Cl 5,15. H 1.76, N 4.07, Cl 5.15.
(b) Når acetyleringen ble utført med rått syr_eklorid og (b) When the acetylation was carried out with crude acid chloride and
ved romtemperatur ble bare en acetylgruppe innført. Utbytte: 66%, sm.p. 238-240 C (tetrahydrofuran).- Funnet: Cl 5,41. Beregnet for C12H10C1J3N2°3: Cl 5,49. at room temperature only one acetyl group was introduced. Yield: 66%, m.p. 238-240 C (tetrahydrofuran).- Found: Cl 5.41. Calculated for C12H10C1J3N2°3: Cl 5.49.
(4) 3- N- (/ 3- acetoksyetyl) - acetamid- 5- N- metylacetamid- 2 , 4, 6- trijodbenzoesyre (4) 3-N-(/3-acetoxyethyl)-acetamide-5-N-methylacetamide-2,4,6-triiodobenzoic acid
3-N- (/3-hydroksyetyl) -acetamid-5-N-metylacetamid-2 ,4,6-trijodbenzoesyre (268 g, 0,4 mol) ble tilsatt i porsjoner til tørr pyridin (500 ml) under omrøring. Oppløsningen ble opphetet til 50°C og eddiksyreanhydrid (80 ml, 0,8 mol) ble tilsatt i dråper i løpet av 30 minutter. Omrøringen ble fortsatt i 1 time hvoretter pyridinet ble avdestillert i vakuum. Den gjenværende olje ble oppløst i vann (1000 ml), og behandlet med benkull ved romtemperatur, filtrert og det O-acylerte produkt ble utfelt med 6n HCl til pH 1,5. Syren filtreres etter omrøring ved romtemperatur i 16 timer og tørkes i vakuum ved 70°C. Utbytte: 235,4 g (82,5%), sm.p. 194-199°C. Omkrystallisert fra dioksan sm.p. 199-201°C. Funnet: C 2 6,84, H 2,54, N 4,01. Beregnet for C,,H,_J.N_0,: C 26,91, H 2,40, N 3,92. 3-N-(β-Hydroxyethyl)-acetamide-5-N-methylacetamide-2,4,6-triiodobenzoic acid (268 g, 0.4 mol) was added portionwise to dry pyridine (500 mL) with stirring. The solution was heated to 50°C and acetic anhydride (80 mL, 0.8 mol) was added dropwise over 30 minutes. The stirring was continued for 1 hour, after which the pyridine was distilled off in vacuo. The remaining oil was dissolved in water (1000 mL), treated with bone charcoal at room temperature, filtered and the O-acylated product was precipitated with 6n HCl to pH 1.5. The acid is filtered after stirring at room temperature for 16 hours and dried in a vacuum at 70°C. Yield: 235.4 g (82.5%), m.p. 194-199°C. Recrystallized from dioxane m.p. 199-201°C. Found: C 2 6.84, H 2.54, N 4.01. Calculated for C,,H,_J.N_0,: C 26.91, H 2.40, N 3.92.
16 17 3 2 6 16 17 3 2 6
Fotnoter til tabell 5: Footnotes to Table 5:
Forbindelse egenskaper i den anførte fremstilling, Compound properties in the stated preparation,
a Opprinnelig utgangsmateriale fremstilt ved N-metyléring av 3-smørsyreamid-2,4,6-trijodbenzoesyre i henhold til britisk a Original starting material prepared by N-methylation of 3-butyric amide-2,4,6-triiodobenzoic acid according to British
patent nr. 987.796. patent No. 987,796.
b Den tilsvarende 3-diacetylamino-2,4,6-trijodbenzoesyre ble fremstilt fra 3-acetamid-2,4,6-trijodbenzoesyre ved behandling b The corresponding 3-diacetylamino-2,4,6-triiodobenzoic acid was prepared from 3-acetamide-2,4,6-triiodobenzoic acid by treatment
med fuktig eddiksyreanhydrid ved 80°C. with moist acetic anhydride at 80°C.
c Den tilsvarende O-acetylerte syre ble fremstilt ved acetylering av 3-N-metylacetamid-5-N-(2,3-dihydroksypropyl)-acetamid-2,4,6-trijodbenzoesyre ved en fremgangsmåte analog fremstilling 4. c The corresponding O-acetylated acid was prepared by acetylation of 3-N-methylacetamide-5-N-(2,3-dihydroxypropyl)-acetamide-2,4,6-triiodobenzoic acid by a method analogous to preparation 4.
Utgangsmaterialene vist i tabell 5 ble anvendt ved fremstilling av røntgenkontrastmidlene anført i tabell 1. Tabell 6 angir de fremgangsmåter som ble anvendt og eksperimentelle detaljer under henvisning til de følgende fremstillingsmåter som viser den spesielle fremgangsmåte som ble anvendt. Den fremgangsmåte som er beskrevet i noen av eksemplene kan naturligvis variere noe med hensyn til uvesentlige trekk. The starting materials shown in Table 5 were used in the preparation of the X-ray contrast agents listed in Table 1. Table 6 indicates the methods used and experimental details with reference to the following preparation methods showing the particular method used. The method described in some of the examples can of course vary somewhat with respect to unimportant features.
Fremstillingsmåte Method of manufacture
( b) Forbindelser i tabell 1 (b) Compounds in Table 1
(5) N-( 3- N- metylacetamid- 2, 4, 6- trijodbenzoyl)- glukamin (5) N-(3-N-methylacetamide-2,4,6-triiodobenzoyl)-glucamine
Syrekloridet fra fremstilling 1 (12 g, 0,02 mol) ble opp-løst i dioksan (120 ml). Til oppløsningen ble tilsatt vann (25 ml) og NaHC03 (1,9 g, 0,022 mol). Glukamin (4,0 g, 0,022 mol) ble tilsatt i delporsjoner og reaksjonsblandingen ble omrørt ved romtemperatur i 24 timer. Oppløsningen ble inndampet til tørrhet i vakuum, residuet oppløst i vann (500 ml), filtrert klart og ført gjennom en Amberlite IR 120 H+ ioneutvekslingskolonne. Det bort-strømmende ble inndampet til tørrhet i vakuum og man fikk et hvitt krystallinsk residuum. Utbytte: 11,7 g (80%), sm.p. 100-120°C. Produktet ble omkrystallisert fra isopropanol (benkullbehandlet i oppløsningen), oppløst i vann og benkullbehandlet ved 100°C i 20 min. Vannet ble avdestillert i vakuum og det hvite residuum tørket i vakuum ved 70°C, sm.p. 120-130°C. The acid chloride from Preparation 1 (12 g, 0.02 mol) was dissolved in dioxane (120 ml). To the solution was added water (25 mL) and NaHCO 3 (1.9 g, 0.022 mol). Glucamine (4.0 g, 0.022 mol) was added in portions and the reaction mixture was stirred at room temperature for 24 hours. The solution was evaporated to dryness in vacuo, the residue dissolved in water (500 mL), filtered clear and passed through an Amberlite IR 120 H+ ion exchange column. The effluent was evaporated to dryness in vacuo and a white crystalline residue was obtained. Yield: 11.7 g (80%), m.p. 100-120°C. The product was recrystallized from isopropanol (treated with bone charcoal in the solution), dissolved in water and treated with bone charcoal at 100°C for 20 min. The water was distilled off in vacuum and the white residue dried in vacuum at 70°C, m.p. 120-130°C.
Funnet: C 26,34, H 3,05, N 3,95, J 51,4 Found: C 26.34, H 3.05, N 3.95, J 51.4
Beregnet for C13H21 : C 26,17, H 2,83, N 3,82, J 51,87 Calculated for C13H21 : C 26.17, H 2.83, N 3.82, J 51.87
(6) N-( 3- diacetylamino- 5- N- metylacetamid- 2, 4, 6- trijodbenzoyl)- N-metylglukamin (6) N-(3-diacetylamino-5-N-methylacetamide-2,4,6-triiodobenzoyl)-N-methylglucamine
Syrekloridet fra fremstilling 3(a) (41,4 g, 0,06 mol) ble The acid chloride from preparation 3(a) (41.4 g, 0.06 mol) was
oppløst i dioksan (750 ml). Til oppløsningen ble tilsatt vann dissolved in dioxane (750 ml). Water was added to the solution
(150 ml) og KHC03 (6,6 g, 0,066 mol) ved omrøring ved romtemperatur. N-metylglukamin (12,9 g, 0,066 mol), ble tilsatt i porsjoner. Etter omrøring i 20 timer ble oppløsningen inndampet til tørrhet i vakuum, residuet oppløst i vann (400 ml) ved 50°C, filtrert klart, pH reguleres til 1 og benkullbehandlet ved romtemperatur i 16 timer, filtrert, filtratet ble ekstrahert med fenol (4 x 50 ml), fenolen vaskes med vann (4 x 40 ml) og fortynnes med eter (600 ml), fenol/eter ble ekstrahert med vann (4 x 50 ml) (150 mL) and KHCO 3 (6.6 g, 0.066 mol) with stirring at room temperature. N-methylglucamine (12.9 g, 0.066 mol) was added in portions. After stirring for 20 hours, the solution was evaporated to dryness in vacuo, the residue dissolved in water (400 ml) at 50°C, filtered clear, pH adjusted to 1 and treated with bone charcoal at room temperature for 16 hours, filtered, the filtrate was extracted with phenol (4 x 50 ml), the phenol is washed with water (4 x 40 ml) and diluted with ether (600 ml), the phenol/ether was extracted with water (4 x 50 ml)
og de forenede vandige lag ble vasket med eter (3 x 30 ml) og inndampet til tørrhet i vakuum. and the combined aqueous layers were washed with ether (3 x 30 mL) and evaporated to dryness in vacuo.
Utbytte: 38,3 g (75%), sm.p. 115-126°C. Produktet ble omkrystallisert fra isopropanol (benkullbehandlet i oppløsning), oppløst i vann, benkullbehandlet ved 60°C, filtratet inndampet til tørrhet og det rensede produkt tørkes i vakuum ved 70°C. Sm.p. 155-165°C. Funnet: J 44,2, beregnet for c2iH28J3N209: J 44,93 Yield: 38.3 g (75%), m.p. 115-126°C. The product was recrystallized from isopropanol (treated with bone charcoal in solution), dissolved in water, treated with bone charcoal at 60°C, the filtrate evaporated to dryness and the purified product dried in vacuum at 70°C. Sm.p. 155-165°C. Found: J 44.2, calculated for c2iH28J3N209: J 44.93
(7) N-( N- metyl- 3, 5- diacetamid- 2, 4, 6- trijodbenzoyl)- N- metyl- (7) N-(N- methyl- 3, 5- diacetamide- 2, 4, 6- triiodobenzoyl)- N- methyl-
glukamin glucamine
Triacetylderivatet fra fremstilling 6 (29 g) ble hydrolysert ved oppløsning i vann ved 60° og tilsetning av 2N natriumhydroksyd-oppløsning i dråper ved pH 10-11 inntil pH stabiliseres ved 10,8. The triacetyl derivative from preparation 6 (29 g) was hydrolyzed by dissolving in water at 60° and adding 2N sodium hydroxide solution dropwise at pH 10-11 until the pH is stabilized at 10.8.
Ved romtemperatur ble pH regulert til 1, oppløsningen benkullbehandlet i 1 time, filtrert og ekstrahert med fenol osv. slik som beskrevet ved fremstilling 6 (4 x 40 ml fenol, 3 x 50 ml vann, 350 ml eter, 4 x 50 mi vann og 2 x 25 ml eter). Det ble isolert 25,8 g (91%), sm.p. 110-130°C. Produktet ble renset som beskrevet i fremstilling 6. Sm.p. 165-170°C. [ a ]J° -4,5 (c 10% i 0,1 n HC1) Funnet: C 28,38, H 3,53, N 5,49, J 47,1 At room temperature, the pH was adjusted to 1, the solution treated with bone charcoal for 1 hour, filtered and extracted with phenol etc. as described in preparation 6 (4 x 40 ml phenol, 3 x 50 ml water, 350 ml ether, 4 x 50 ml water and 2 x 25 ml ether). 25.8 g (91%) were isolated, m.p. 110-130°C. The product was purified as described in Preparation 6. M.p. 165-170°C. [ a ]J° -4.5 (c 10% in 0.1 n HC1) Found: C 28.38, H 3.53, N 5.49, J 47.1
Beregnet for C^H^J^Og: C 28,34, H 3,26, N 5,22, J 42,29 Calculated for C^H^J^Og: C 28.34, H 3.26, N 5.22, J 42.29
(8) N-[ 3- N- (/ 3- hydroksyetyl) - acetamid- 5- N- metylacetamid- 2 , 4, 6-trijodbenzoyl]- N- metyl- 2, 3- dihydroksypropylamin (8) N-[3-N-(/3-hydroxyethyl)-acetamide-5-N-methylacetamide-2,4,6-triiodobenzoyl]-N-methyl-2,3-dihydroxypropylamine
3-N- (/3-acetoksyetyl) -acetamid-5-N-metylacetamid-2 , 4, 6-trijodbenzoylklorid (28,3 g, 0,04 mol) ble oppløst i dioksan (280 ml). Vann (60 ml) og KHC03 (4,4 g, 0,044 mol) ble tilsatt under om-røring. Til denne oppløsning ble N-metyl-2,3-dihydroksy-propyl- 3-N-(β-acetoxyethyl)-acetamide-5-N-methylacetamide-2,4,6-triiodobenzoyl chloride (28.3 g, 0.04 mol) was dissolved in dioxane (280 mL). Water (60 mL) and KHCO 3 (4.4 g, 0.044 mol) were added with stirring. To this solution was added N-methyl-2,3-dihydroxy-propyl-
amin (4,63 g, 0,044 mol) oppløst i.dioksan (5 ml) tilsatt i dråper ved romtemperatur ijløpet :av 15 minutter. Omrøringen ble fortsatt i 16 timer; Oppløsningen ble inndampet til tørrhet, residuet oppløst i vann (-200 ml) , filtrert klårt, oppløsningen opphetes til 60°C og" 2n natriumhydroksydoppløsning ble tilsatt i amine (4.63 g, 0.044 mol) dissolved in dioxane (5 mL) was added dropwise at room temperature over 15 minutes. Stirring was continued for 16 hours; The solution was evaporated to dryness, the residue dissolved in water (-200 ml), filtered clear, the solution heated to 60°C and 2N sodium hydroxide solution was added in
dråper (pH 10-11) inntil pH ble stabil ved 10,5. Ved pH 1 ble oppløsningen benkullbehandlet i i time ved romtemperatur. Filtratet ble inndampet med fenol som tidligere beskrevet. Den erholdte vandige oppløsning ble benkullbehandlet ved romtemperatur i 16 timer og inndampet til tørrhet. Utbytte: 25,5 g (84%), sm.p. 140-145°C. Funnet: C 28,70%, H 3,75% N 5,45%, J 50,3% Beregnet' for C18H24J3N306:C 28,51, H 3,19, N 5,54, J 50,2. (9) 3, 5- bis[ N-( 2', 3'- dihydroksypropyl)- N- metylkarbamoyl]- N-. drops (pH 10-11) until the pH became stable at 10.5. At pH 1, the solution was treated with bone charcoal for 1 hour at room temperature. The filtrate was evaporated with phenol as previously described. The obtained aqueous solution was treated with bone charcoal at room temperature for 16 hours and evaporated to dryness. Yield: 25.5 g (84%), m.p. 140-145°C. Found: C 28.70%, H 3.75% N 5.45%, J 50.3% Calculated' for C18H24J3N306: C 28.51, H 3.19, N 5.54, J 50.2. (9) 3,5-bis[N-(2',3'-dihydroxypropyl)-N-methylcarbamoyl]-N-.
( 2'- hydroksyetyl)- 2, 4, 6- trijodacetanilid (2'- hydroxyethyl)- 2, 4, 6- triiodoacetanilide
3,5-bis[N-(2',3'-dihydroksypropyl)-N-metylkarbamoyl]-2,4,6-trijodacetanilid (3,9 g, 5 m mol) ble oppløst i vann (8 ml) og derpå ble tilsatt 5n natriumhydroksyd (3 ml) og 2-kloretanol (0,67 ml,.10 m mol). Etter to døgn ved romtemperatur ble opp-løsningen ansyr et med 6n saltsyre og inndampet til tørrhet i vakuum..Residuet ble oppløst i vann (15 ml) og ekstrahert med fenol (4x5 ml), de forenede fenolekstrakter ble vasket med vann og fortynnet med eter (60 ml). Denne fenol-eter blanding ble ekstrahert med vann (4 x 10 ml) som sluttlig ble vasket med eter. Derpå ble den vandige oppløsning inndampet i vakuum til 3,5-bis[N-(2',3'-dihydroxypropyl)-N-methylcarbamoyl]-2,4,6-triiodacetanilide (3.9 g, 5 mmol) was dissolved in water (8 mL) and then 5N sodium hydroxide (3 mL) and 2-chloroethanol (0.67 mL, 10 mmol) were added. After two days at room temperature, the solution was acidified with 6N hydrochloric acid and evaporated to dryness in vacuo. The residue was dissolved in water (15 ml) and extracted with phenol (4x5 ml), the combined phenol extracts were washed with water and diluted with ether (60 ml). This phenol-ether mixture was extracted with water (4 x 10 ml) which was finally washed with ether. The aqueous solution was then evaporated in vacuo
tørrhet. Utbytte: 1,6 g (40%). Sm.p. 146-159°C. dryness. Yield: 1.6 g (40%). Sm.p. 146-159°C.
(Funnet: C 29,26, H 3,67, J 46,2, N 5,08. (Found: C 29.26, H 3.67, J 46.2, N 5.08.
Beregnet for C^H^J^Og: C 29,32, H 3,45, J 46,47, N 5,13). Calculated for C^H^J^Og: C 29.32, H 3.45, J 46.47, N 5.13).
forts. continued
Ytterligere fremstillingsmåter Additional manufacturing methods
(10) N-( 3 <5- diacetamid- 2, 4, 6- trijodbenzoyl)- N- metylglukamin (10) N-(3<5-diacetamide-2,4,6-triiodobenzoyl)-N-methylglucamine
(a) N-( 3, 5- dinitrobenzoyl)- N- metylglukamin (a) N-(3,5-dinitrobenzoyl)-N-methylglucamine
N-metylglukamin (21,4 g, 0,11 mol) ble suspendert i N-methylglucamine (21.4 g, 0.11 mol) was suspended in
DMF (200 ml). Trietylamin (11,5 g, 0,11 mol) ble tilsatt. Til DMF (200 mL). Triethylamine (11.5 g, 0.11 mol) was added. To
denne suspensjon ble ved 4 tilsatt under omrøring 3,5-dinitro-benzoylklorid (23,0 g, 0,1 mol) oppløst i dioksan (100 ml). Temperaturen steg til 10°. Omrøringen ble fortsatt ved denne temperatur i 2 timer etterfulgt av 16 timer ved romtemperatur. Trietylaminhydroklorid ble filtrert fra og DMF destillert av fra filtratet. Residuet, en lysebrun olje, ble oppløst i vann (200 ml), to this suspension was added at 4 with stirring 3,5-dinitro-benzoyl chloride (23.0 g, 0.1 mol) dissolved in dioxane (100 ml). The temperature rose to 10°. Stirring was continued at this temperature for 2 hours followed by 16 hours at room temperature. Triethylamine hydrochloride was filtered off and DMF distilled off from the filtrate. The residue, a light brown oil, was dissolved in water (200 mL),
pH regulert til 1 og oppløsningen ekstrahert med fenol i henhold til vanlige arbeidsmåter. Den erholdte vandige oppløsning ble behandlet med benkull ved romtemperatur i 24 timer og filtratet inndampet til tørrhet i vakuum. Residuet - en lysebrun olje - pH adjusted to 1 and the solution extracted with phenol according to standard procedures. The obtained aqueous solution was treated with bone charcoal at room temperature for 24 hours and the filtrate evaporated to dryness in vacuo. The residue - a light brown oil -
ble ytterligere tørket i vakuum ved 65°. Utbytte: 25,5 g (65%). IR-spektrum viste et karakteristisk karbonylabsorbsjonsbånd ved 1670-1620 cm<-1>. was further dried in vacuo at 65°. Yield: 25.5 g (65%). IR spectrum showed a characteristic carbonyl absorption band at 1670-1620 cm<-1>.
Rf-verdi: 0,55 - 0,6 (papir, n-BuOH : EtOH : NH^ : H20 =4:1:2:1). Rf value: 0.55 - 0.6 (paper, n-BuOH : EtOH : NH 2 : H 2 O =4:1:2:1).
(b) N-( 3, 5- diamino- 2, 4, 6- trijodbenzoyl)- N- metylglukamin (b) N-(3,5-diamino-2,4,6-triiodobenzoyl)-N-methylglucamine
Produktet fra trinn (a) (7,78 g, 0,02 mol) ble oppløst i metanol (150 ml) og hydrogenert ved romtemperatur og 3 kg/cm 2 i løpet av 16 timer. Katalysator 1 g 5% Pd/C. Katalysatoren ble filtrert fra, filtratet behandlet med benkull ved pH 2 og metanolen avdestilleres i vakuum. Residuet - en lysegul olje - ble oppløst i vann, ansyret til pH mindre enn 1 og behandlet med benkull ved romtemperatur. Et papirkromatogram (n-BuOH : EtOH : NH^ : H20 = 4:1:2:1) viste det ønskede produkt med R^-verdi 0,14. The product from step (a) (7.78 g, 0.02 mol) was dissolved in methanol (150 ml) and hydrogenated at room temperature and 3 kg/cm 2 during 16 hours. Catalyst 1 g 5% Pd/C. The catalyst was filtered off, the filtrate treated with bone charcoal at pH 2 and the methanol distilled off in a vacuum. The residue - a pale yellow oil - was dissolved in water, acidified to pH less than 1 and treated with bone charcoal at room temperature. A paper chromatogram (n-BuOH : EtOH : NH^ : H 2 O = 4:1:2:1) showed the desired product with an R^ value of 0.14.
Filtratet ble i løpet av 15 minutter tilsatt en 3,75n NaJCl2~ oppløsning (17,6 ml, 3,3 ekv.). Det joderte produkt skilte seg ut som en mørkebrun olje. Reaksjonsblandingen lot man henstå ved 3°, den ovenstående væske ble dekantert fra og. oljen tørket i hØyvakuum ved romtemperatur. Oljen krystalliserte under denne prosess. Utbytte: 7,5 g (53%), sm.p. 110°. A 3.75 n NaJCl 2 solution (17.6 ml, 3.3 eq.) was added to the filtrate over 15 minutes. The iodinated product separated as a dark brown oil. The reaction mixture was allowed to stand at 3°, the supernatant liquid was decanted from and. the oil dried in high vacuum at room temperature. The oil crystallized during this process. Yield: 7.5 g (53%), m.p. 110°.
(c) N-( 3, 5- diacetamid- 2, 4, 6- trijodbenzoyl- N- metylglukamin (c) N-(3,5-diacetamide-2,4,6-triiodobenzoyl-N-methylglucamine
Produktet fra trinn (b) (3 g, 4,2 mmol) ble suspendert i eddiksyreanhydrid (30 ml). Etter omrøring ved romtemperatur i 1 time ble konsentrert H2S04 (0,3 ml) tilsatt. Alt materiale ble oppløst. Omrøringen ble fortsatt i 16 timer før eddiksyre-anhydridet ble destillert av i vakuum'. Det oljeaktige residuum ble oppløst i ln natriumhydroksydoppløsning (100 ml), ansyres til pH 1 med 6n saltsyre, behandlet med benkull ved romtemperatur og filtratet ekstrahert med fenol. Den erholdte vandige oppløsning ble inndampet til tørrhet i vakuum og residuet - et gråaktig krystallinsk produkt - ble tørket i vakuum ved 70°. Utbytte: 0,9 g (27%), sm.p. 145-165°. Omkrystallisert fra metanol, sm.p. 155-167°. The product from step (b) (3 g, 4.2 mmol) was suspended in acetic anhydride (30 mL). After stirring at room temperature for 1 hour, concentrated H 2 SO 4 (0.3 mL) was added. All material was dissolved. Stirring was continued for 16 hours before the acetic anhydride was distilled off in vacuo. The oily residue was dissolved in 1N sodium hydroxide solution (100 ml), acidified to pH 1 with 6N hydrochloric acid, treated with bone charcoal at room temperature and the filtrate extracted with phenol. The resulting aqueous solution was evaporated to dryness in vacuo and the residue - a greyish crystalline product - was dried in vacuo at 70°. Yield: 0.9 g (27%), m.p. 145-165°. Recrystallized from methanol, m.p. 155-167°.
Denne forbindelse viser identisk IR-spektrum og kromatografiske data når den blir sammenlignet med forbindelse 49 This compound shows identical IR spectrum and chromatographic data when compared to compound 49
i tabell 6 som ble fremstilt ved å la utgangsmateriale 13 reagere med N-metyl-glukamin. in Table 6 which was prepared by reacting starting material 13 with N-methyl-glucamine.
(11) N-( 2, 4, 6- trij odbenzoyl)- N- metylglukamin (11) N-(2,4,6-triiodobenzoyl)-N-methylglucamine
(a) 2, 4, 6- trijodbenzoylklorid (a) 2, 4, 6-triiodobenzoyl chloride
2,4,6-trijodbenzoesyre (15 g) ble suspendert i tionylklorid (75 ml) og behandlet under tilbakeløp. 30 minutter etter igangsettingen var materialet oppløst, reaksjonsoppløsningen ble avkjølt og inndampet i vakuum. Residuet ble oppløst i varm benzen (40 ml), avkjølt til romtemperatur, filtrert og filtratet inndampet i vakuum. Utbytte: 13,6 g. 2,4,6-triiodobenzoic acid (15 g) was suspended in thionyl chloride (75 ml) and refluxed. 30 minutes after initiation, the material was dissolved, the reaction solution was cooled and evaporated in vacuo. The residue was dissolved in hot benzene (40 ml), cooled to room temperature, filtered and the filtrate evaporated in vacuo. Yield: 13.6 g.
I.R. (KBr): 1785 cm" (-C0C1). I.R. (KBr): 1785 cm" (-C0C1).
(b) N-( 2, 4, 6- trijodbenzoyl)- N- metylglukamin (b) N-(2,4,6-triiodobenzoyl)-N-methylglucamine
2,4,6-trijodbenzoylklorid (13,6 g, 26,2 mmol) ble oppløst 2,4,6-triiodobenzoyl chloride (13.6 g, 26.2 mmol) was dissolved
1 DMF (30 ml) og avkjølt i isvann. Kaliumkarbonat (4,0 g, 1 DMF (30 ml) and cooled in ice water. Potassium carbonate (4.0 g,
29 mmol) ble tilsatt under omrøring og derpå ble N-metyl-glukamin (5,65 g, 29 mmol) tilsatt i løpet av 90 minutter. Etter 4 timer fikk temperaturen anledning til å stige til romtemperatur. Etter 2 døgn ble suspensjonen filtrert, og filtratet inndampet i vakuum. Residuet ble oppløst i vann (75 ml) og pH regulert til ca. 0,5 - 1,0 med saltsyre. Ansyringen medførte en utfeining av en gummiaktig substans som krystalliserte når den ble behandlet med metanol. Sluttlig ble produktet suspendert i vann (25 ml) i 2 timer. Utbytte: 11,7 g (66%). Sm.p. 178-190°. 29 mmol) was added with stirring and then N-methyl-glucamine (5.65 g, 29 mmol) was added over 90 minutes. After 4 hours the temperature was allowed to rise to room temperature. After 2 days, the suspension was filtered, and the filtrate evaporated in vacuo. The residue was dissolved in water (75 ml) and the pH adjusted to approx. 0.5 - 1.0 with hydrochloric acid. The acidification led to a refinement of a gummy substance which crystallized when treated with methanol. Finally, the product was suspended in water (25 ml) for 2 hours. Yield: 11.7 g (66%). Sm.p. 178-190°.
IR (KBr): 1620 cm"<1> (CON), bredt bånd ved 3300 cm<-1> )OH). IR (KBr): 1620 cm"<1> (CON), broad band at 3300 cm<-1> )OH).
(Funnet: C 24,17, H 2,75, J 57,0, N 2,26 (Found: C 24.17, H 2.75, J 57.0, N 2.26
Beregnet for C14H1Q<J>3<N>06: C 24,84, H 2,68, J 56,28, N 2,0<7>. Calculated for C14H1Q<J>3<N>06: C 24.84, H 2.68, J 56.28, N 2.0<7>.
Fremstilling 12 Production 12
3, 5- bis-[ N-( 2, 3- dihydroksypropyl)- N- metylkarbamyl1- 2, 4, 6- trij od-acetanilid ( forbindelse 9) 3, 5- bis-[ N-(2, 3- dihydroxypropyl)- N- methylcarbamyl1- 2, 4, 6- triiodo-acetanilide (compound 9)
Syreklorid nr. 11 fra tabell 4 (3,2 g, 0,005 mol) ble opp-løst i dimetylformamid (10 ml) og avkjølt i is-vann. Kaliumkarbonat (1,52 g, 0,011 mol) ble.tilsatt under omrøring. En opp-løsning av 3-metylamino-propandiol-2,3 (1,16 g, 0,011 mol) i dimetylformamid (85 ml) ble tilsatt i løpet av 15 minutter. Etter 4 timer fikk temperaturen anledning til å stige til romtemperatur og omrøringen fortsatte i ytterligere 20 timer. Blandingen ble filtrert, filtratet inndampet til tørrhet i vakuum og residuet ekstrahert med fenol på vanlig måte. Den erholdte vandige opp-løsning ble inndampet til tørrhet i vakuum for å gi 1,5 g (39%) av de ønskede produkt. Sm.p. 60-75°C (spaltn.). Dette produkt ble oppløst i metanol (10% oppløsning) og oppløsningen fortynnet med isopropanol (2 ganger volumet), dekantert fra de utfelte, fargede forurensninger og inndampet til tørrhet i vakuum. Residuet ble oppløst i vann, behandlet med benkull, inndampet til tørrhet i vakuum, påny oppløst i vann, behandlet påny med benkull og filtratet inndampet til tørrhet i vakuum. Sm.p. 135-159°. Funnet: C 28,29, Acid chloride No. 11 from Table 4 (3.2 g, 0.005 mol) was dissolved in dimethylformamide (10 ml) and cooled in ice-water. Potassium carbonate (1.52 g, 0.011 mol) was added with stirring. A solution of 3-methylamino-propanediol-2,3 (1.16 g, 0.011 mol) in dimethylformamide (85 mL) was added over 15 minutes. After 4 hours the temperature was allowed to rise to room temperature and stirring continued for a further 20 hours. The mixture was filtered, the filtrate evaporated to dryness in vacuo and the residue extracted with phenol in the usual manner. The resulting aqueous solution was evaporated to dryness in vacuo to give 1.5 g (39%) of the desired product. Sm.p. 60-75°C (decomposition). This product was dissolved in methanol (10% solution) and the solution diluted with isopropanol (2 times the volume), decanted from the precipitated colored impurities and evaporated to dryness in vacuo. The residue was dissolved in water, treated with bone charcoal, evaporated to dryness in vacuo, redissolved in water, treated again with bone charcoal and the filtrate evaporated to dryness in vacuum. Sm.p. 135-159°. Found: C 28,29,
H 3,52, N 5,60, J 48,5. Beregnet for <C>18<H>24<J>3<N>3<0>7<:> C 27,89, H 3.52, N 5.60, J 48.5. Calculated for <C>18<H>24<J>3<N>3<0>7<:> C 27.89,
H 3,12, N 5,42, J 49,11. H 3.12, N 5.42, J 49.11.
(13) N-( N- metyl- 3, 5- diacetamid)- 2, 4, 6- trijodbenzoyl)- glukosamin (13) N-(N- methyl- 3, 5- diacetamide)- 2, 4, 6- triiodobenzoyl)- glucosamine
Syreklorid fra fremstilling 3 (41,3 g, 0,06 mol) ble Acid chloride from Preparation 3 (41.3 g, 0.06 mol) was
bragt til å reagere med glukosamin og hydrolysert som beskrevet for forbindelse 10. Utbytte: 36,0 g (76%). reacted with glucosamine and hydrolyzed as described for compound 10. Yield: 36.0 g (76%).
(14) N-( N- metyl- 3, 5- diacetamid- 2, 4, 6- trijodbenzoyl)- glukosamin ( metode nr. 2 (14) N-(N- methyl- 3, 5- diacetamide- 2, 4, 6- triiodobenzoyl)- glucosamine ( method no. 2
N-metyl-3,5-diacetamid-2,4,6-trijodbenzoylklorid (32,3 g, 0,05 mol) ble oppløst i DMF (300 ml) ved 0°C. Spor som ble uopp-løst. Kaliumkarbonat (13,8 g, 0,1 mol) og glukosaminhydroklorid (10,8 g, 0,05 mol) ble tilsatt. Suspensjonen ble omrørt ved 0° i 2 timer og derpå ved romtemperatur i ytterligere 20 timer. Kaliumkarbonat (2,76 g, 0,02 mol) og glukosaminhydroklorid (2,15 g, N-Methyl-3,5-diacetamide-2,4,6-triiodobenzoyl chloride (32.3 g, 0.05 mol) was dissolved in DMF (300 mL) at 0 °C. Traces that were unsolved. Potassium carbonate (13.8 g, 0.1 mol) and glucosamine hydrochloride (10.8 g, 0.05 mol) were added. The suspension was stirred at 0° for 2 hours and then at room temperature for a further 20 hours. Potassium carbonate (2.76 g, 0.02 mol) and glucosamine hydrochloride (2.15 g,
0,01 mol) ble tilsatt og omrøringen ble fortsatt ved romtemperatur i 46 timer. Total reaksjonstid: 68 timer. 0.01 mol) was added and stirring was continued at room temperature for 46 hours. Total reaction time: 68 hours.
Anorganiske salter ble filtrert fra og filtratet inndampet til tørrhet i vakuum ved 50-55°. Residuet ble oppløst i vann Inorganic salts were filtered off and the filtrate evaporated to dryness in vacuo at 50-55°. The residue was dissolved in water
(200 ml), ansyret ved hjelp av saltsyre til pH 1 og behandlet med benkull ved romtemperatur i 16 timer. Den vandige oppløsning ble ekstrahert med fenol som foran beskrevet. Den erholdte vandige ekstrakt (pH ca. 4) ble behandlet med benkull i 20 minutter ved 80°. Det svakt fargede filtrat ble inndampet til tørrhet i vakuum (200 ml), acidified with hydrochloric acid to pH 1 and treated with bone charcoal at room temperature for 16 hours. The aqueous solution was extracted with phenol as described above. The aqueous extract obtained (pH approx. 4) was treated with bone charcoal for 20 minutes at 80°. The faintly colored filtrate was evaporated to dryness in vacuo
og residuet tørkes i vakuum ved romtemperatur i 24 timer. Utbytte; 31,0 g (78%). Smp. 165-230° (spaltn.). Det rå produkt ble blandet med 20 vekt/vekt prosent filter-hjelpemiddel (speedex) og ekstrahert i et Soxhlet-apparat med tetrahydrofuran i 20 timer. Utbytte: 65%. Produktet ble ytterligere renset ved omkrystalli-sering fra isopropanol, oppløst i vann og behandlet med benkull først i 3 timer ved romtemperatur, derpå i 30 minutter ved 80-90° og sluttelig i 16 timer ved romtemperatur. Den fargeløse, vandige oppløsning ble inndampet til tørrhet i vakuum og det hvite, krystallinske residuum tørkes i vakuum først ved romtemperatur og derpå ved 70°. Sm.p„ 230° (spaltn.). and the residue is dried in vacuum at room temperature for 24 hours. Dividend; 31.0 g (78%). Temp. 165-230° (dec.). The crude product was mixed with 20 w/w percent filter aid (speedex) and extracted in a Soxhlet apparatus with tetrahydrofuran for 20 hours. Yield: 65%. The product was further purified by recrystallization from isopropanol, dissolved in water and treated with bone charcoal first for 3 hours at room temperature, then for 30 minutes at 80-90° and finally for 16 hours at room temperature. The colorless, aqueous solution was evaporated to dryness in vacuo and the white, crystalline residue was dried in vacuo first at room temperature and then at 70°. Sm.p„ 230° (splitn.).
= 18,0° (K = 10% i 0,ln HC1, i likevekt med hensyn til mutarotasjon). = 18.0° (K = 10% in 0.ln HC1, in equilibrium with respect to mutarotation).
Tynnsjiktkromatografi (Silica F, n-BuOH : H20 : AcOH = Thin layer chromatography (Silica F, n-BuOH : H2O : AcOH =
100 : 50 : 22) viste 15-20% endo isomer (Rf 0,44) og 80-85% ekso isomer (Rf 0,68), bekreftet ved kjernemagnetisk resonans. 100 : 50 : 22) showed 15-20% endo isomer (Rf 0.44) and 80-85% exo isomer (Rf 0.68), confirmed by nuclear magnetic resonance.
(15) N-( 3- acetamido- 5- N- metylkarbamoyl- 2, 4, 6- trijodbenzoyl)-N-( 2- hydroksyetyl)- glukamin (15) N-(3-acetamido-5-N-methylcarbamoyl-2,4,6-triiodobenzoyl)-N-(2-hydroxyethyl)-glucamine
3-acetamido-5-N-metylkarbamoyl-2,4,6-trijodbenzoylklorid 3-acetamido-5-N-methylcarbamoyl-2,4,6-triiodobenzoyl chloride
(18,4 g, 29mmol) ble suspendert i dimetylformamid (100 ml) og avkjølt i isvann. Derefter ble kaliumkarbonat (4,6 g, 33 m mol) (18.4 g, 29 mmol) was suspended in dimethylformamide (100 mL) and cooled in ice water. Then potassium carbonate (4.6 g, 33 m mol)
og N-(2-hydroksyetyl)-glukamin (8 g, 36 m mol) tilsatt. Blandin- and N-(2-hydroxyethyl)-glucamine (8 g, 36 m mol) added. Blendin-
gen ble kraftig omrørt. Efter 4 timer fikk temperaturen stige til romtemperatur. Blandingen ble omrørt i to dager og deretter filt- gen was vigorously stirred. After 4 hours the temperature was allowed to rise to room temperature. The mixture was stirred for two days and then felt-
rert. Filtratet ble inndampet i vakuum til tørrhet, og residuet ble oppløst i vann (50 ml). Derefter ble den vandige oppløsning surgjort med saltsyre og ekstrahert med fenol (4 x 25 ml). De samlede fenolekstrakter ble vasket med vann, derefter fortynnet med eter (300 ml) og ekstrahert med vann (5 x 30 ml). Endelig ble det vandige lag vasket med eter (4 x 20 ml) og inndampet til tørrhet i vakuum. correct. The filtrate was evaporated in vacuo to dryness, and the residue was dissolved in water (50 ml). The aqueous solution was then acidified with hydrochloric acid and extracted with phenol (4 x 25 mL). The combined phenolic extracts were washed with water, then diluted with ether (300 mL) and extracted with water (5 x 30 mL). Finally, the aqueous layer was washed with ether (4 x 20 mL) and evaporated to dryness in vacuo.
Utbytte: 18,9 g (79%). Yield: 18.9 g (79%).
Produktet ble oppløst i 80 prosentig (volum/volum) The product was dissolved in 80 percent (volume/volume)
vandig metanol (180 ml) og omrørt med "Dowex" anionebytteharpiks 1x4 (5 g). Den neste dag var pH ca. 7,1. Efter filtrering ble "Amberlite" kationebytterharpiks IR 120 H (2 g) tilsatt, og suspensjonen ble omrørt i 2 timer. Oppløsningens pH var ca. 3,5. aqueous methanol (180 ml) and stirred with "Dowex" anion exchange resin 1x4 (5 g). The next day the pH was approx. 7.1. After filtration, "Amberlite" cation exchange resin IR 120 H (2 g) was added and the suspension was stirred for 2 hours. The pH of the solution was approx. 3.5.
Derefter ble "Dowex" anionebytterharpiks (2,5 g) tilsatt. Efter Then "Dowex" anion exchange resin (2.5 g) was added. After
at blandingen var omrørt i flere timer, var pH steget til 6,1. that the mixture had been stirred for several hours, the pH had risen to 6.1.
Efter filtrering ble "Amberlite" IR 120 H (2 g) tilsatt, og blan- After filtration, "Amberlite" IR 120 H (2 g) was added, and mixed
dingen ble omrørt i ca. 2 timer. pH sank til 4,4. Derefter ble "Dowex" anionebytterharpiks (2 g) tilsatt, blandingen ble omrørt i to timer og filtrert (pH var ca. 6,1). Ionebytterharpiksene ble oppsamlet på et filter og vasket med 80 prosentig (volum/vo- The thing was stirred for approx. 2 hours. The pH dropped to 4.4. Then "Dowex" anion exchange resin (2 g) was added, the mixture was stirred for two hours and filtered (pH was about 6.1). The ion exchange resins were collected on a filter and washed with 80 percent (v/v)
lum) vandig metanol. De filtrerte oppløsninger ble samlet og inndampet til tørrhet i vakuum. Utbytte: 15,7 g. Produktet ble omkrystallisert fra isopropylalkohol .(120 ml). Utbytte: 11 g. lum) aqueous methanol. The filtered solutions were collected and evaporated to dryness in vacuo. Yield: 15.7 g. The product was recrystallized from isopropyl alcohol (120 ml). Yield: 11 g.
Produktet (10 g) ble oppløst i vann (10 ml) og ekstrahert tre The product (10 g) was dissolved in water (10 ml) and extracted wood
ganger med en blanding av kloroform og butanol (60:40). Derefter ble det vandige lag inndampet til tørrhet i vakuum. Produktet ble oppløst på nytt i vann og inndampet til tørrhet i vakuum to ganger. Utbytte: 9,0 g. Smp.: 178-190°C. (Funnet: I 45,8. times with a mixture of chloroform and butanol (60:40). The aqueous layer was then evaporated to dryness in vacuo. The product was redissolved in water and evaporated to dryness in vacuo twice. Yield: 9.0 g. M.p.: 178-190°C. (Found: In 45.8.
Beregnet for CigH26I3N3Og: I 46,36. Calculated for CigH26I3N3Og: I 46.36.
Claims (8)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB3269969 | 1969-06-27 | ||
GB613070 | 1970-02-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO129093B true NO129093B (en) | 1974-02-25 |
Family
ID=26240463
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO02518/70A NO129093B (en) | 1969-06-27 | 1970-06-26 |
Country Status (19)
Country | Link |
---|---|
US (1) | US3701771A (en) |
JP (1) | JPS5147702B1 (en) |
AT (1) | AT318134B (en) |
BE (1) | BE752574A (en) |
BR (1) | BR7020080D0 (en) |
CA (1) | CA935153A (en) |
CH (1) | CH544551A (en) |
DE (1) | DE2031724C3 (en) |
DK (1) | DK130709B (en) |
ES (1) | ES381202A1 (en) |
FI (1) | FI53066C (en) |
FR (1) | FR2053037B1 (en) |
HK (1) | HK65978A (en) |
IE (1) | IE34927B1 (en) |
IL (1) | IL34803A (en) |
IT (1) | IT1047908B (en) |
NL (1) | NL153083B (en) |
NO (1) | NO129093B (en) |
SE (1) | SE392100B (en) |
Families Citing this family (75)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE795555A (en) * | 1972-02-16 | 1973-08-16 | Schering Ag | TRIIODO-ISOPHTALOYL-MONOAMINO-ACID AMIDES, THEIR PREPARATION PROCESS AND THEIR USE |
US3914294A (en) * | 1972-06-01 | 1975-10-21 | Squibb & Sons Inc | 3,5-Disubstituted-2,4,6-triiodobenzoic acids |
GB1495679A (en) * | 1974-06-17 | 1977-12-21 | Mallinckrodt Inc | Substituted isophthalamic acids |
US4138589A (en) * | 1974-06-17 | 1979-02-06 | Mallinckrodt, Inc. | Substituted isophthalamic acids |
US4125709A (en) * | 1974-10-04 | 1978-11-14 | Mallinckrodt, Inc. | Polyhydroxy-alkyl-3,5-disubstituted-2,4,6-triiodocarbanilates |
CH608189A5 (en) * | 1974-12-13 | 1978-12-29 | Savac Ag | |
GB1491129A (en) * | 1975-06-04 | 1977-11-09 | Guerbet Sa | Iodo-benzene derivatives and an x-ray contrast medium containing them |
US4314055A (en) * | 1975-09-29 | 1982-02-02 | Mallinckrodt, Inc. | 3,5-Disubstituted-2,4,6-triiodoanilides of polyhydroxy-monobasic acids |
US4307072A (en) * | 1976-03-12 | 1981-12-22 | Mallinckrodt, Inc. | N-Triiodobenzoylaminoacyl polyhydroxic amines |
GB1548594A (en) * | 1976-06-11 | 1979-07-18 | Nyegaard & Co As | Triiodoisophthalic acid amides |
DE2628517C2 (en) * | 1976-06-23 | 1985-02-21 | Schering AG, 1000 Berlin und 4709 Bergkamen | Dicarboxylic acid bis (3,5-dicarbamoyl-2,4,6-triiodanilide) compounds, process for their preparation and X-ray contrast media |
US4125599A (en) * | 1976-08-19 | 1978-11-14 | Mallinckrodt, Inc. | X-ray contrast agents |
JPS53137793A (en) * | 1977-05-07 | 1978-12-01 | Nihon Seikan Kk | Method of attaching container lid indicating plate |
JPS54128855U (en) * | 1978-02-16 | 1979-09-07 | ||
DE2909439A1 (en) * | 1979-03-08 | 1980-09-18 | Schering Ag | NEW NON-ionic x-ray contrast agents |
US4256729A (en) * | 1979-03-23 | 1981-03-17 | Mallinckrodt, Inc. | N,N'-Bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-5-(2-keto-L-gulonamido)isophthalamide and radiological compositions containing same |
US4284620A (en) | 1979-03-23 | 1981-08-18 | Mallinckrodt, Inc. | N-(2-Hydroxyethyl)-2,4,6-triiodo-3,5-bis-(2-keto-L-gulonamido)benzamide and radiological compositions containing same |
US4243653A (en) * | 1979-04-27 | 1981-01-06 | The Regents Of The University Of California | Non-ionic polyiodo sugar substituted anilines |
DE2928417A1 (en) * | 1979-07-12 | 1981-01-29 | Schering Ag | TRIJODIZED BASES |
IT1193211B (en) * | 1979-08-09 | 1988-06-15 | Bracco Ind Chimica Spa | 2,4,6-TRIIODE-ISOPHTHALIC ACID DERIVATIVES, METHOD FOR THEIR PREPARATION AND CONTRAST MEANS THAT CONTAIN THEM |
DE3001292A1 (en) * | 1980-01-11 | 1981-07-16 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | NON-ionic 5-C SUBSTITUTED 2,4,6-TRIJOD ISOPHTHALIC ACID DERIVATIVES |
DE3001293A1 (en) * | 1980-01-11 | 1981-07-16 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | IONIC 5-C SUBSTITUTED 2,4,6-TRIJOD ISOPHTAL ACID DERIVETE |
US4341756A (en) * | 1980-01-31 | 1982-07-27 | The Regents Of The University Of California | Novel amino-dioxepane intermediates for the synthesis of new non-ionic contrast media |
DE3038853A1 (en) | 1980-10-10 | 1982-05-27 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW N-HYDROXY-ALKYLATED DICARBONIC ACID-BIS- (3,5-DICARBAMOYL-2,4,6-TRIJODANILIDES), THEIR PRODUCTION AND THEIR CONTAINING X-RAY CONTRAST AGENTS (II) |
DE3150917A1 (en) * | 1981-12-18 | 1983-06-30 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | "2-AMINO-1- (1,3-DIOXOLAN-4-YL) -ETHANOL COMPOUNDS, THEIR PRODUCTION AND USE FOR PROCESSING" |
DE3150916A1 (en) * | 1981-12-18 | 1983-06-30 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | N-HYDROXYAETHYLATED 2,4,6-TRIJODAMINOISIOPHTHALIC ACID-BISTRIHYDROXYBUTYLAMIDES, THEIR PRODUCTION AND THEIR CONTAINING X-RAY CONTRASTING AGENTS " |
EP0108638B1 (en) * | 1982-11-08 | 1986-07-16 | NYEGAARD & CO. A/S | X-ray contrast agents |
US5191119A (en) * | 1983-10-20 | 1993-03-02 | Cook Imaging Corp. | Process for producing non-ionic radiographic contrast media utilizing N-allylation |
US4584401A (en) * | 1983-10-20 | 1986-04-22 | Biophysica Foundation | Methods and compositions involving polyhydroxylated polyiodo non-ionic contrast media |
DE3447970C1 (en) * | 1984-02-29 | 1988-06-30 | Dr. Franz Koehler Chemie Gmbh, 6146 Alsbach, De | N-(3,5-Diacetamido-2,4,6-triiodobenzoyl)amino acid esters, process for their preparation and their use |
US5035877A (en) * | 1985-08-09 | 1991-07-30 | Cook Imaging Corporation | Non-ionic contrast media from ionic contrast media |
US4954348A (en) * | 1985-08-09 | 1990-09-04 | Cook Imaging Corporation | Non-ionic polyol contrast media from ionic contrast media |
DE3689330T2 (en) * | 1985-08-09 | 1994-05-19 | Cook Imaging Corp | NON-ionic POLYOL CONTRAST AGENTS FROM IONIC CONTRAST AGENTS. |
JPS63166908U (en) * | 1987-04-17 | 1988-10-31 | ||
FR2614299B1 (en) * | 1987-04-23 | 1989-08-18 | Guerbet Sa | IODINE DIAMINO BENZENIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND CONTRAST PRODUCTS CONTAINING THEM. |
IE63232B1 (en) * | 1987-05-22 | 1995-04-05 | Bracco Int Bv | A process for the preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives and corresponding novel 5-acylamino-2,4,6-triiodo or tribromo-benzoic acid derivatives obtained by said process |
US5043152A (en) * | 1988-06-02 | 1991-08-27 | Guerbet S.A. | Novel iodinated non-ionic triiodobenzene compounds and contrast media containing them |
US5698739A (en) * | 1989-07-05 | 1997-12-16 | Schering Aktiengesellschaft | Carboxamide non-ionic contrast media |
FR2649698B1 (en) * | 1989-07-17 | 1991-10-25 | Guerbet Sa | NOVEL POLYIODIC NON-ION DERIVATIVES WITH ARYLSULFONAMIDE STRUCTURE AND CONTRAST PRODUCT CONTAINING THEM |
GB8919929D0 (en) | 1989-09-04 | 1989-10-18 | Nycomed As | Compositions |
US5869024A (en) * | 1989-11-29 | 1999-02-09 | Bracco International B.V. | Methods and compositions for using non-ionic contrast agents to reduce the risk of clot formation in diagnostic procedures |
US5614638A (en) * | 1989-11-29 | 1997-03-25 | Bracco International B.V. | Nonionic radiographic contrast agents |
US4997983A (en) * | 1990-01-31 | 1991-03-05 | Mallinckrodt, Inc. | Process for production of ioversol |
US5527926A (en) * | 1990-11-26 | 1996-06-18 | Bracco International B.V. | Methods and compositions for using non-ionic contrast agents to reduce the risk of clot formation in diagnostic procedures |
US5278311A (en) * | 1992-06-05 | 1994-01-11 | E. R. Squibb & Sons, Inc. | Nonionic radiographic contrast agents |
US5668196A (en) * | 1995-08-10 | 1997-09-16 | Nanosystems Llc | 3-amido-triiodophenyl esters as x-ray contrast agents |
US5925683A (en) * | 1996-10-17 | 1999-07-20 | Target Therapeutics, Inc. | Liquid embolic agents |
US6051210A (en) | 1997-05-15 | 2000-04-18 | Bracco Research Usa | N,N-dimethyldiatrizoic acid and its conjugates as hepatobiliary agents for X-ray CT imaging |
DE19731591C2 (en) * | 1997-07-17 | 1999-09-16 | Schering Ag | Pharmaceutical compositions containing triiodoaromatics containing perfluoroalkyl groups and their use in tumor therapy and interventional radiology |
US6309420B1 (en) | 1997-10-14 | 2001-10-30 | Parallax Medical, Inc. | Enhanced visibility materials for implantation in hard tissue |
US7572263B2 (en) | 1998-04-01 | 2009-08-11 | Arthrocare Corporation | High pressure applicator |
WO1999049819A1 (en) | 1998-04-01 | 1999-10-07 | Parallax Medical, Inc. | Pressure applicator for hard tissue implant placement |
US6751290B2 (en) | 1998-09-08 | 2004-06-15 | Veritas Pharmaceuticals, Inc. | Radiographic assessment of tissue after exposure to a compound |
US6226352B1 (en) | 1998-09-08 | 2001-05-01 | Veritas Pharmaceuticals, Inc. | System and method for radiographic imaging of tissue |
US6723746B2 (en) * | 1998-09-08 | 2004-04-20 | Veritas Pharmaceuticals, Inc. | Functional radiographic imaging methods and agents |
US20040170561A1 (en) * | 1998-09-08 | 2004-09-02 | Jesse Salb | Functional radiographic imaging methods and agents |
AU6168699A (en) | 1999-03-24 | 2000-10-09 | Parallax Medical, Inc. | Non-compliant system for delivery of implant material |
AU6058000A (en) * | 1999-07-12 | 2001-01-30 | Scimed Life Systems, Inc. | Liquid based vaso-occlusive compositions |
US6783515B1 (en) | 1999-09-30 | 2004-08-31 | Arthrocare Corporation | High pressure delivery system |
EP1263324B1 (en) | 2000-03-16 | 2009-12-02 | Veritas Pharmaceuticals | Radiographic assessment of tissue response to compounds |
US6660248B2 (en) | 2000-11-10 | 2003-12-09 | William Marsh Rice University | Fullerene (C60)-based X-ray contrast agent for diagnostic imaging |
US20070191964A1 (en) * | 2001-04-04 | 2007-08-16 | Arthrocare Corporation | Enhanced visibility materials for implantation in hard tissue |
US7341716B2 (en) * | 2002-04-12 | 2008-03-11 | Boston Scientific Scimed, Inc. | Occlusive composition |
US7632291B2 (en) | 2003-06-13 | 2009-12-15 | Trivascular2, Inc. | Inflatable implant |
US20050283182A1 (en) * | 2004-06-21 | 2005-12-22 | Concentric Medical, Inc. | Systems and methods for intraluminal delivery of occlusive elements |
CN101098916A (en) | 2005-01-13 | 2008-01-02 | 金文申有限公司 | Composite materials containing carbon nanoparticles |
CN101646402A (en) * | 2007-01-19 | 2010-02-10 | 金文申有限公司 | Porous, the non-degradable implant made with powdered moulding |
CA2677699A1 (en) * | 2007-02-28 | 2008-09-04 | Cinvention Ag | High surface cultivation system |
WO2008104599A1 (en) * | 2007-02-28 | 2008-09-04 | Cinvention Ag | High surface cultivation system bag |
US8753390B2 (en) | 2007-03-15 | 2014-06-17 | OrthoSpace Ltd. | Methods for implanting a prosthesis in a human shoulder |
CN102336681B (en) * | 2011-07-21 | 2013-11-13 | 浙江司太立制药股份有限公司 | Triiodobenzene compound contrast agent |
US9289307B2 (en) | 2011-10-18 | 2016-03-22 | Ortho-Space Ltd. | Prosthetic devices and methods for using same |
CN102516116B (en) * | 2011-11-22 | 2013-11-13 | 浙江司太立制药股份有限公司 | Low-osmotic-pressure triiodo-benzene compound contrast agent |
WO2017046647A1 (en) | 2015-09-18 | 2017-03-23 | Ortho-Space Ltd. | Intramedullary fixated subacromial spacers |
WO2018138561A1 (en) | 2017-01-30 | 2018-08-02 | Ortho-Space Ltd. | Processing machine and methods for processing dip-molded articles |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR6777M (en) * | 1967-07-10 | 1969-03-10 |
-
1970
- 1970-06-26 IE IE834/70A patent/IE34927B1/en unknown
- 1970-06-26 NL NL707009493A patent/NL153083B/en not_active IP Right Cessation
- 1970-06-26 US US50075A patent/US3701771A/en not_active Expired - Lifetime
- 1970-06-26 IL IL34803A patent/IL34803A/en unknown
- 1970-06-26 CH CH973270A patent/CH544551A/en not_active IP Right Cessation
- 1970-06-26 BE BE752574D patent/BE752574A/en not_active IP Right Cessation
- 1970-06-26 FR FR7023704A patent/FR2053037B1/fr not_active Expired
- 1970-06-26 FI FI1802/70A patent/FI53066C/fi active
- 1970-06-26 SE SE7008921A patent/SE392100B/en unknown
- 1970-06-26 AT AT577970A patent/AT318134B/en not_active IP Right Cessation
- 1970-06-26 ES ES381202A patent/ES381202A1/en not_active Expired
- 1970-06-26 JP JP45055344A patent/JPS5147702B1/ja active Pending
- 1970-06-26 NO NO02518/70A patent/NO129093B/no unknown
- 1970-06-26 BR BR220080/70A patent/BR7020080D0/en unknown
- 1970-06-26 DE DE2031724A patent/DE2031724C3/en not_active Expired
- 1970-06-26 CA CA086599A patent/CA935153A/en not_active Expired
- 1970-06-26 IT IT51731/70A patent/IT1047908B/en active
- 1970-06-26 DK DK332470AA patent/DK130709B/en not_active IP Right Cessation
-
1978
- 1978-11-16 HK HK659/78A patent/HK65978A/en unknown
Also Published As
Publication number | Publication date |
---|---|
FI53066B (en) | 1977-10-31 |
US3701771A (en) | 1972-10-31 |
ES381202A1 (en) | 1973-04-16 |
IL34803A (en) | 1975-03-13 |
NL153083B (en) | 1977-05-16 |
JPS5147702B1 (en) | 1976-12-16 |
DE2031724A1 (en) | 1971-01-07 |
SE392100B (en) | 1977-03-14 |
AT318134B (en) | 1974-09-25 |
CA935153A (en) | 1973-10-09 |
CH544551A (en) | 1973-11-30 |
BE752574A (en) | 1970-12-28 |
FR2053037A1 (en) | 1971-04-16 |
BR7020080D0 (en) | 1973-03-13 |
DK130709B (en) | 1975-04-01 |
DE2031724B2 (en) | 1978-11-02 |
IT1047908B (en) | 1980-10-20 |
NL7009493A (en) | 1970-12-29 |
IE34927L (en) | 1970-12-27 |
IE34927B1 (en) | 1975-10-01 |
IL34803A0 (en) | 1970-08-19 |
DK130709C (en) | 1975-09-01 |
FI53066C (en) | 1978-02-10 |
FR2053037B1 (en) | 1974-08-09 |
HK65978A (en) | 1978-11-24 |
DE2031724C3 (en) | 1979-06-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NO129093B (en) | ||
US4021481A (en) | Amido derivatives of 2,4,6-triiodobenzoic acids containing at least one N-hydroxyalkyl and at least two hydroxyl groups | |
EP0015867B1 (en) | Diamides of triiodo-isophthalic acids, their preparation and x-ray contrast agents containing them | |
US3702866A (en) | Novel 3,5 - bis-acylamido - 2,4,6-triiodobenzoic acids and 5-acylamido-2,4,6-triiodoisophthalamic acids | |
CA1123009A (en) | Derivatives of 2,4,6-triiodo-isophthalic acid, processes for their synthesis and x-ray contrasting materials containing these | |
CA1106401A (en) | Dicarboxylic acid bis-(3,5-dicarbamoyl-2,4,6- triiodoanilides) | |
DK150504B (en) | TRIJODISOPHYLIC ACID DERIVATIVES USED AS XENTIC CONTRACTORS AND RADIOLOGICAL PREPARATIONS CONTAINING THESE | |
DK147336B (en) | 5-HYDROXYPROPIONYLAMINO-2,4,6-TRIIOD ISOPHTHALIC ACID BIS (DIHYDROXYPROPYLAMIDES) FOR USE IN ROENTINE CONTRAST AGENTS AND ROENTGEN CONTRAST AGENTS CONTAINING THESE COMPOUNDS | |
AU616203B2 (en) | New dicarboxylic acid-bis(3,5-dicarbamoyl-2,4,6- triiodoanilides), process for their production as well as x- ray contrast media containing them | |
PL124023B1 (en) | Process for manufacturing novel derivatives of glycerin | |
DE2523567A1 (en) | CONTRAST AGENTS FOR X-RAY PHOTOS | |
US4005188A (en) | X-ray contrast media | |
DE2624153C2 (en) | N, N'-acylamido-triiodo-benzoylated alkylenediamines, process for their preparation and their use as contrast media for X-rays | |
NO158182B (en) | NON-IONIC 5-C SUBSTITUTED 2,4,6-TRIODISOPHTHALIC ACID DERIVATIVES AND ROENTGEN CONTRAST AGENTS CONTAINING THESE. | |
DE69200168T2 (en) | Polyiodine compounds, process for their preparation and contrast media containing them. | |
US3076024A (en) | Acylated 3, 5-diaminopolyhalobenzoic acids | |
EP1124790A1 (en) | Biodegradable nonionic contrast media | |
NO853953L (en) | R¯NTGENKONTRASTMIDLER. | |
DE69807138T2 (en) | Benzoamide derivative, antiulcus and antibacterial agents | |
US2913451A (en) | Iodophenylamidoalkanesulfonic acid compounds | |
JPH10279548A (en) | Alkylene diamine derivative, and antiulcer agent antibacterial agent | |
DK174745B1 (en) | Non-ionic contrast media based on ionic contrast media | |
DE69214934T2 (en) | NON-IONIC X-RAY RADIANT CONTRAST, METHOD FOR THE PRODUCTION THEREOF AND COMPOSITIONS CONTAINING THE SAME | |
US3647864A (en) | 5-substituted-1 3-benzenediacrylic and -dipropionic acids | |
US3446837A (en) | 3 - (n - substituted - acylamino) - 2,4,6 - triiodophenyl fatty acid compounds |